Ionizable lipid compounds

ABSTRACT

Provided herein is a class of ionizable lipid compounds represented by formula (IV), or pharmaceutically acceptable salts, isotopic variants, tautomers or stereoisomers thereof. Also provided is a nanoparticle pharmaceutical composition comprising said compound, and the application of said compound and its composition in the delivery of nucleic acids.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application claims the priority of the Chinese PatentApplication No. 202210478559.X filed on Apr. 29, 2022, Chinese PatentApplication No. 202210478132.X filed on Apr. 29, 2022, Chinese PatentApplication No. 202211319669.8 filed on Oct. 26, 2022, and ChinesePatent Application No. 202211419893.4 filed on Nov. 14, 2022. TheChinese Patent Applications mentioned above are incorporated herein byreference as part of the disclosure of the present application.

FIELD OF THE INVENTION

The present disclosure relates to anew class of ionizable cationic lipidcompounds, or pharmaceutically acceptable salts, isotopic variants,tautomers or stereoisomers thereof. The present disclosure also relatesto lipid nanoparticles and pharmaceutical compositions comprising saidcompound, and the application of the lipid nanoparticles in the deliveryof biologically active substances such as nucleic acids (e.g., mRNA,miRNA, siRNA, saRNA, ASO, and DNA, etc.).

BACKGROUND OF THE INVENTION

Gene therapy refers to the introduction of exogenous genes into targetcells to correct or compensate for genetic defects or abnormalitieswithin the cell, so as to achieve the purpose of treatment. In the pastfew decades, research related to the treatment of clinical diseasesthrough gene therapy has received more and more attention. Especially inrecent years, siRNA-related drugs and mRNA vaccines have been approvedby the FDA for clinical treatment, which has further promoted researchand related investment in the field of gene therapy.

Nucleic acid substances are easily degraded by nucleases in organisms,and nucleic acid substances themselves are negatively charged, whichmakes it difficult for them to enter the cell through the cell membrane.As a nucleic acid delivery material, lipid nanoparticles (LNP) are oneof the most important nucleic acid delivery systems with the advantagesof easy to prepare, good biodegradability, no immunogenicity and goodsafety.

The nucleic acid vaccine developed by Moderna and BioNTech uses LNP asthe delivery system, and the main components of LNP include cationiclipids, cholesterol, neutral lipids and polyethylene glycol-conjugatedlipids. Among them, cationic lipid molecules are the core of LNPdelivery system, and their molecular structure plays a decisive role inthe delivery efficiency, targeting, and formulation stability, and thelike, of the entire liposome nanoparticles.

Due to the different requirements of the delivery system for thedelivery of different kinds of nucleic acid substances and the specificdelivery of different targets, in order to meet the different needs ofgene therapy, new lipid molecules need to be further developed.

SUMMARY OF THE INVENTION

The present disclosure develops a new class of ionizable cationic lipidcompounds that can be used to deliver various biologically activesubstances with high delivery efficiency.

In one aspect, the present disclosure provides a compound of formula(IV), or a pharmaceutically acceptable salt, isotopic variant, tautomeror stereoisomer thereof:

-   -   wherein,    -   M₁ and M₂ are independently selected from —C(O)O—, —O—,        —SC(O)O—, —OC(O)NR_(a)—, —NR_(a)C(O)NR_(a)—, —OC(O)S—, —OC(O)O—,        —NR_(a)C(O)O—, —OC(O)—, —SC(O)—, —C(O)S—, —NR_(a)—,        —C(O)NR_(a)—, —NR_(a)C(O)—, —NR_(a)C(O)S—, —SC(O)NR_(a)—,        —C(O)—, —OC(S)—, —C(S)O—, —OC(S)NR_(a)—, —NR_(a)C(S)O—, —S—S—        and —S(O)₀₋₂—;    -   Q is selected from a chemical bond, —C(O)O—, —O—, —SC(O)O—,        —OC(O)NR_(b)—, —NR_(b)C(O)NR_(b)—, —OC(O)S—, —OC(O)O—,        —NR_(b)C(O)O—, —OC(O)—, —SC(O)—, —C(O)S—, —NR_(b)—,        —C(O)NR_(b)—, —NR_(b)C(O)—, —NR_(b)C(O)S—, —SC(O)NR_(b)—,        —C(O)—, —OC(S)—, —C(S)O—, —OC(S)NR_(b)—, —NR_(b)C(S)O—, —S—S—,        —S(O)₀₋₂—, phenylene and pyridylidene, wherein, the phenylene or        pyridylidene is optionally substituted with one or more R*;    -   G₅ is a chemical bond or C₁₋₈ alkylene, which is optionally        substituted with one or more R**;    -   G_(6a) and G_(6b) are independently a chemical bond or C₁₋₇        alkylene, which is optionally substituted with one or more R**;    -   G_(6a) and G_(6b) have a total length of 0, 1, 2, 3, 4, 5, 6 or        7 carbon atoms;    -   R₉, R₁₀ and R** are independently H, C₁₋₈ alkyl, -L_(c)-OR_(c),        -L_(c)-SR_(c) or -L_(c)-NR_(c)R′_(c);    -   G₁, G₂, G₃ and G₄ are independently a chemical bond, C₁₋₁₃        alkylene, C₂₋₁₃ alkenylene or C₂₋₁₃ alkynylene, which is        optionally substituted with one or more R^(s);    -   G₁ and G₂ have a total length of 3, 4, 5, 6, 7, 8, 9, 10, 11, 12        or 13 carbon atoms;    -   G₃ and G₄ have a total length of 3, 4, 5, 6, 7, 8, 9, 10, 11, 12        or 13 carbon atoms;    -   R₃ and R₄ are independently H, C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl,        C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, 3- to 14-membered cycloalkyl, 3-        to 14-membered heterocyclyl, C₆₋₁₀ aryl or 5- to 14-membered        heteroaryl, which is optionally substituted with one or more R*:    -   or, R₃ and R₄ are taken together with the N atom to which they        are attached to form 3- to 14-membered heterocyclyl, which is        optionally substituted with one or more R*;    -   or, R₄ and R₉ are taken together with the atoms to which they        are attached to form 3- to 14-membered heterocyclyl or 5- to        14-membered heteroaryl, which is optionally substituted with one        or more R*;    -   R* is independently H, halogen, cyano, C₁₋₁₀ alkyl, C₁₋₁₀        haloalkyl, -L_(b)-OR_(b), -L_(b)-SR_(b) or -L_(b)-NR_(b)R′_(b);    -   R₅, R₆, R₇ and R₈ are independently C₁₋₈ alkyl, which is        optionally substituted with one or more R*;    -   R₁ and R₂ are independently C₄₋₂₀ alkyl, C₄₋₂₀ alkenyl or C₄₋₂₀        alkynyl, which is optionally substituted with one or more R, and        wherein one or more methylene units are optionally and        independently replaced with —NR″—;    -   R^(s) is independently H, C₁₋₁₄ alkyl, -L_(d)-OR_(d),        -L_(d)-SR_(d) or -L_(d)-NR_(d)R′_(d);    -   R is independently H, C₁₋₂₀ alkyl, -L_(a)-OR_(a), -L_(a)-SR_(a)        or -L_(a)-NR_(a)R′_(a);    -   R″ is independently H or C₁₋₂₀ alkyl;    -   L_(a) and L_(e) are independently a chemical bond or C₁₋₂₀        alkylene;    -   L_(b) and L_(f) are independently a chemical bond or C₁₋₁₀        alkylene;    -   L_(c) is independently a chemical bond or C₁₋₈ alkylene;    -   L_(d) is independently a chemical bond or C₁₋₁₄ alkylene;    -   R_(a) and R′_(a) are independently selected from H, C₁₋₂₀ alkyl,        3- to 14-membered cycloalkyl, and 3- to 14-membered        heterocyclyl, which are optionally substituted with one or more        of the following substituents: H, C₁₋₂₀ alkyl, -L_(e)-OR_(e),        -L_(c)-SR_(e) and -L_(c)-NR_(e)R′_(e);    -   R_(b) and R′_(b) are independently selected from H, C₁₋₁₀ alkyl,        3- to 14-membered cycloalkyl, and 3- to 14-membered        heterocyclyl, which are optionally substituted with one or more        of the following substituents: H, C₁₋₁₀ alkyl, -L_(f)-OR_(f),        -L_(f)-SR_(f) and -L_(f)-NR_(f)R′_(f);    -   R_(c) and R′_(c) are independently H or C₁₋₈ alkyl;    -   R_(d) and R′_(d) are independently H or C₁₋₁₄ alkyl;    -   R_(e) and R′_(e) are independently H or C₁₋₂₀ alkyl;    -   R_(f) and R′_(f) are independently H or C₁₋₁₀ alkyl.

In another aspect, the present disclosure provides a nanoparticlecomposition, the nanoparticle composition comprises lipid components,and optionally comprises a load; wherein, the lipid component comprisesthe compounds of the present disclosure.

U.S. Ser. No. 11/246,933B1 discloses that the incorporation of thebiodegradable group(s) into the tail chain of a lipid compound in alipid nanoparticle results in faster metabolism and removal of the lipidfrom the body following delivery of the active agent to a target area.As a result, these lipids which contain the biodegradable groups havelower toxicity than similar lipids without the biodegradable groups. Thetail chain of the cationic lipid compound of the present disclosure hasbiodegradable group(s), thereby has superior toxicity profile to similarlipids without biodegradable groups, such as DLin-MC3-DMA.

In another aspect, the present disclosure provides a pharmaceuticalcomposition comprising a compound of the present disclosure or ananoparticle composition of the present disclosure, and optionallypharmaceutically acceptable excipient(s), such as carrier(s),adjuvant(s) or vehicle(s).

In another aspect, the present disclosure provides the use of a compoundof the present disclosure, a nanoparticle composition of the presentdisclosure, or a pharmaceutical composition of the present disclosure inthe manufacture of a medicament for treating, diagnosing, or preventinga disease.

In another aspect, the present disclosure provides the use of a compoundof the present disclosure, a nanoparticle composition of the presentdisclosure, or a pharmaceutical composition of the present disclosure inthe manufacture of a medicament for delivering a load.

In another aspect, the present disclosure provides a method of treating,diagnosing, or preventing a disease in a subject, comprisingadministering to the subject a compound of the present disclosure, ananoparticle composition of the present disclosure, or a pharmaceuticalcomposition of the present disclosure.

In another aspect, the present disclosure provides a compound of thepresent disclosure, a nanoparticle composition of the presentdisclosure, or a pharmaceutical composition of the present disclosure,for use in treating, diagnosing, and/or preventing a disease.

In another aspect, the present disclosure provides a method ofdelivering a load in a subject, comprising administering to the subjecta compound of the present disclosure, a nanoparticle composition of thepresent disclosure, or a pharmaceutical composition of the presentdisclosure.

In another aspect, the present disclosure provides a compound of thepresent disclosure, a nanoparticle composition of the presentdisclosure, or a pharmaceutical composition of the present disclosure,for use in delivering a load.

In a specific embodiment, the load is one or more of therapeutic agents,prophylactic agents, or diagnostic agents; alternatively, thetherapeutic agent, prophylactic agent, or diagnostic agent is a nucleicacid.

In a more specific embodiment, the nucleic acid is one or more of ASO,RNA or DNA.

In a more specific embodiment, the RNA is selected from one or more ofinterfering RNA (RNAi), small interfering RNA (siRNA), short hairpin RNA(shRNA), antisense RNA (aRNA), messenger RNA (mRNA), modified messengerRNA (mmRNA), long non-coding RNA (lncRNA), microRNA (miRNA), smallactivating RNA (saRNA), multimeric coding nucleic acid (MCNA), polymericcoding nucleic acid (PCNA), guide RNA (gRNA), CRISPRRNA (crRNA) andnucleases, alternatively mRNA, more alternatively modified mRNA.

Terminology Chemical Terminology

Terminology of specific functional groups and chemical terms aredescribed in more detail below.

When a range of values is listed, it is intended to encompass each valueand sub-range within the range. For example, “C₁₋₆ alkyl” is intended toinclude C₁, C₂, C₃, C₄, C₅, C₆, C₁₋₆, C₁₋₅, C₁₋₄, C₁₋₃, C₁₋₂, C₂₋₆,C₂₋₅, C₂₋₄, C₂₋₃, C₃₋₆, C₃₋₅, C₃₋₄, C₄₋₆, C₄₋₅ and C₅₋₆ alkyl.

“C₁₋₂₈ alkyl” refers to a radical of a linear or branched, saturatedhydrocarbon group having 1 to 28 carbon atoms. In some embodiments,C₄₋₂₈ alkyl, C₄₋₂₄ alkyl, C₄₋₂₀ alkyl, C₈₋₁₀ alkyl, C₂₋₈ alkyl, C₇₋₉alkyl, C₄₋₆ alkyl, C₁₋₂₀ alkyl, C₁₋₁₄ alkyl, C₂₋₁₄ alkyl, C₁₋₁₃ alkyl,C₁₋₁₂ alkyl, C₁₋₁₀ alkyl, C₁₋₈ alkyl, C₁₋₇ alkyl, C₂₋₇ alkyl, C₁₋₆alkyl, C₁₋₅ alkyl, C₅ alkyl, C₁₋₄ alkyl, C₂₋₄ alkyl, C₁₋₃ alkyl, C₂₋₃alkyl, C₁₋₂ alkyl and Me are alternative. Examples of C₁₋₆ alkyl includemethyl (C₁), ethyl (C₂), n-propyl (C₃), iso-propyl (C₃), n-butyl (C₄),tert-butyl (C₄), sec-butyl (C₄), iso-butyl (C₄), n-pentyl (C₅), 3-pentyl(C₅), pentyl (C₅), neopentyl (C₅), 3-methyl-2-butyl (C₅), tert-pentyl(C₅) and n-hexyl (C₆). The term “C₁₋₆ alkyl” also includes heteroalkyl,wherein one or more (e.g., 1, 2, 3 or 4) carbon atoms are substitutedwith heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon,phosphorus). Alkyl groups can be optionally substituted with one or moresubstituents, for example, with 1 to 5 substituents, 1 to 3 substituentsor 1 substituent. Conventional abbreviations of alkyl include Me (—CH₃),Et (—CH₂CH₃), iPr (—CH(CH₃)₂), nPr (—CH₂CH₂CH₃), n-Bu (—CH₂CH₂CH₂CH₃) ori-Bu (—CH₂CH(CH₃)₂).

“C₂₋₂₀ alkenyl” refers to a radical of a linear or branched hydrocarbongroup having 2 to 20 carbon atoms and at least one carbon-carbon doublebond. “C₄₋₂₈ alkenyl” refers to a radical of a linear or branchedhydrocarbon group having 4 to 28 carbon atoms and at least onecarbon-carbon double bond. In some embodiments, C₄₋₂₀ alkenyl, C₂₋₁₃alkenyl, C₂₋₁₀ alkenyl, C₂₋₆ alkenyl, and C₂₋₄ alkenyl is alternative.Examples of C₂₋₆ alkenyl include vinyl (C₂), 1-propenyl (C₃), 2-propenyl(C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), pentenyl (C₅),pentadienyl (C₅), hexenyl (C₆), etc. The term “C₂₋₆ alkenyl” alsoincludes heteroalkenyl, wherein one or more (e.g., 1, 2, 3 or 4) carbonatoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen,boron, silicon, phosphorus). The alkenyl groups can be optionallysubstituted with one or more substituents, for example, with 1 to 5substituents, 1 to 3 substituents or 1 substituent.

“C₂₋₂₀ alkynyl” refers to a radical of a linear or branched hydrocarbongroup having 2 to 20 carbon atoms, at least one carbon-carbon triplebond and optionally one or more carbon-carbon double bonds. “C₄₋₂₈alkynyl” refers to a radical of a linear or branched hydrocarbon grouphaving 4 to 28 carbon atoms, at least one carbon-carbon triple bond andoptionally one or more carbon-carbon double bonds. In some embodiments,C₄₋₂₀ alkynyl, C₂₋₁₃ alkynyl, C₂₋₁₀ alkynyl, C₂₋₆ alkynyl, and C₂₋₄alkynyl is alternative. Examples of C₂₋₆ alkynyl include, but are notlimited to, ethynyl (C₂), 1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl(C₄), 2-butynyl (C₄), pentynyl (C₅), hexynyl (C₆), etc. The term “C₂₋₆alkynyl” also includes heteroalkynyl, wherein one or more (e.g., 1, 2, 3or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur,nitrogen, boron, silicon, phosphorus). The alkynyl groups can besubstituted with one or more substituents, for example, with 1 to 5substituents, 1 to 3 substituents or 1 substituent.

“C₁₋₂₀ alkylene” refers to a divalent group formed by removing anotherhydrogen of the C₁₋₂₀ alkyl, and can be substituted or unsubstituted. Insome embodiments, C₄₋₂₀ alkylene, C₈₋₁₀ alkylene, C₂₋₈ alkylene, C₇₋₉alkylene, C₄₋₆ alkylene, C₁₋₂₀ alkylene, C₁₋₁₄ alkylene, C₂₋₁₄ alkylene,C₁₋₁₃ alkylene, C₁₋₁₂ alkylene, C₁₋₁₀ alkylene, C₁₋₈ alkylene, C₁₋₇alkylene, C₂₋₇ alkylene, C₁₋₆ alkylene, C₁₋₅ alkylene, C₅ alkylene, C₁₋₄alkylene, C₂₋₄ alkylene, C₁₋₃ alkylene, C₂₋₃ alkylene, C₁₋₂ alkylene,and methylene are alternative. The unsubstituted alkylene groupsinclude, but are not limited to, methylene (—CH₂—), ethylene (—CH₂CH₂—),propylene (—CH₂CH₂CH₂—), butylene (—CH₂CH₂CH₂CH₂—), pentylene(—CH₂CH₂CH₂CH₂CH₂—), hexylene (—CH₂CH₂CH₂CH₂CH₂CH₂—), etc. Examples ofsubstituted alkylene groups, such as those substituted with one or morealkyl (methyl) groups, include, but are not limited to, substitutedmethylene (—CH(CH₃)—, —C(CH₃)₂—), substituted ethylene (—CH(CH₃)CH₂—,—CH₂CH(CH₃)—, —C(CH₃)₂CH₂—, —CH₂C(CH₃)₂—), substituted propylene(—CH(CH₃)CH₂CH₂—, —CH₂CH(CH₃)CH₂—, —CH₂CH₂CH(CH₃)—, —C(CH₃)₂CH₂CH₂—,—CH₂C(CH₃)₂CH₂—, —CH₂CH₂C(CH₃)₂—), etc.

“C₂₋₁₃ alkenylene” refers to a C₂₋₁₃ alkenyl group wherein anotherhydrogen is removed to provide a divalent radical of alkenylene, andwhich may be substituted or unsubstituted. In some embodiments, C₂₋₁₀alkenyl, C₂₋₆ alkenyl, and C₂₋₄ alkenylene is yet alternative. Exemplaryunsubstituted alkenylene groups include, but are not limited to,ethylene (—CH═CH—) and propenylene (e.g., —CH═CHCH₂—, —CH₂—CH═CH—).Exemplary substituted alkenylene groups, e.g., substituted with one ormore alkyl (methyl) groups, include but are not limited to, substitutedethylene (—C(CH₃)═CH—, —CH═C(CH₃)—), substituted propylene (e.g.,—C(CH₃)═CHCH₂—, —CH═C(CH₃)CH₂—, —CH═CHCH(CH₃)—, —CH═CHC(CH₃)₂—,—CH(CH₃)—CH═CH—, —C(CH₃)₂—CH═CH—, —CH₂—C(CH₃)═CH—, —CH₂—CH═C(CH₃)—), andthe like.

“C₂₋₁₃ alkynylene” refers to a C₂₋₁₃ alkynyl group wherein anotherhydrogen is removed to provide a divalent radical of alkynylene, andwhich may be substituted or unsubstituted. In some embodiments, C₂₋₁₀alkynylene, C₂₋₆ alkynylene, and C₂₋₄ alkynylene is yet alternative.Exemplary alkynylene groups include, but are not limited to, ethynylene(—C≡C—), substituted or unsubstituted propynylene (—C—CCH₂—), and thelike.

“C₀₋₆ alkylene” refers to the chemical bond and the “C₁₋₆ alkylene”described above, “C₀₋₄ alkylene” refers to the chemical bond and the“C₁₋₄ alkylene” described above.

The term “variable A and variable B have a total length of x carbonatoms” means that the total number of carbon atoms of the main chain inthe group represented by variable A and the number of carbon atoms ofthe main chain in the group represented by variable B is x.

“Halo” or “halogen” refers to fluorine (F), chlorine (Cl), bromine (Br)and iodine (I).

Thus, “C₁₋₁₀ haloalkyl” refers to the above “C₁₋₁₀ alkyl”, which issubstituted by one or more halogen. In some embodiments, C₁₋₆ haloalkyland C₁₋₄ haloalkyl is yet alternative, and still alternatively C₁₋₂haloalkyl. Exemplary haloalkyl groups include, but are not limited to,—CF₃, —CH₂F, —CHF₂, —CHFCH₂F, —CH₂CHF₂, —CF₂CF₃, —CCl₃, —CH₂Cl, —CHCl₂,2,2,2-trifluoro-1,1-dimethyl-ethyl, and the like. The haloalkyl can besubstituted at any available point of attachment, for example, with 1 to5 substituents, 1 to 3 substituents or 1 substituent.

“C₃₋₁₄ cycloalkyl” or “3- to 14-membered cycloalkyl” refers to a radicalof a non-aromatic cyclic hydrocarbon group having from 3 to 14 ringcarbon atoms and zero heteroatoms, optionally wherein 1, 2 or 3 doubleor triple bonds are contained. In some embodiments, 3- to 10-memberedcycloalkyl, 5- to 10-membered cycloalkyl, 3- to 8-membered cycloalkyl,3- to 7-membered cycloalkyl, 3- to 6-membered cycloalkyl are yetalternative, and still alternatively 5- to 7-membered cycloalkyl, 4- to6-membered cycloalkyl, 5- to 6-membered cycloalkyl, 5-memberedcycloalkyl, and 6-membered cycloalkyl. The cycloalkyl also includes aring system in which the cycloalkyl ring described above is fused withone or more aryl or heteroaryl groups, wherein the point of attachmentis on the cycloalkyl ring, and in such case, the number of carbon atomscontinues to represent the number of carbon atoms in the cycloalkylsystem. The cycloalkyl further comprises the cycloalkyl described above,in which the substituents on any non-adjacent carbon atoms are connectedto form a bridged ring, together forming a polycyclic alkane sharing twoor more carbon atoms. The cycloalkyl further comprises the cycloalkyldescribed above, in which the substituents on the same carbon atom areconnected to form a ring, together forming a polycyclic alkane sharingone carbon atom. Exemplary cycloalkyl groups include, but are notlimited to, cyclopropyl (C₃), cyclopropenyl (C₃), cyclobutyl (C₄),cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₆), cyclohexyl(C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆), cycloheptyl (C₇),cycloheptenyl (C₇), cycloheptadienyl (C₇), cycloheptatrienyl (C₇), etc.The cycloalkyl can be substituted with one or more substituents, forexample, with 1 to 5 substituents, 1 to 3 substituents or 1 substituent.

“C₃₋₁₀ cycloalkylene” refers to a divalent radical formed by removinganother hydrogen of C₃₋₁₀ cycloalkyl group and may be substituted orunsubstituted. In some embodiments, C₃₋₆ cycloalkylene and C₃₋₄cycloalkylene groups are particularly alternative, especiallyalternatively cyclopropylene.

“3- to 14-membered heterocyclyl” refers to a saturated or unsaturatedradical of 3- to 14-membered non-aromatic ring system having ring carbonatoms and 1 to 5 ring heteroatoms, wherein each of the heteroatoms isindependently selected from nitrogen, oxygen, sulfur, boron, phosphorusand silicon, optionally wherein 1, 2 or 3 double or triple bonds arecontained. In the heterocyclyl containing one or more nitrogen atoms,the point of attachment can be a carbon or nitrogen atom as long as thevalence permits. In some embodiments, 3- to 10-membered heterocyclyl isalternative, which is a radical of 3- to 10-membered non-aromatic ringsystem having ring carbon atoms and 1 to 5 ring heteroatoms; in someembodiments, 5- to 10-membered heterocyclyl is alternative, which is aradical of 5- to 10-membered non-aromatic ring system having ring carbonatoms and 1 to 5 ring heteroatoms; in some embodiments, 3- to 8-memberedheterocyclyl is alternative, which is a radical of 3- to 8-memberednon-aromatic ring system having ring carbon atoms and 1 to 4 ringheteroatoms; in some embodiments, 3- to 7-membered heterocyclyl isalternative, which is a radical of 3- to 7-membered non-aromatic ringsystem having ring carbon atoms and 1 to 4 ring heteroatoms; 5- to7-membered heterocyclyl is alternative, which is a radical of 5- to7-membered non-aromatic ring system having ring carbon atoms and 1 to 3ring heteroatoms; 3- to 6-membered heterocyclyl is alternative, which isa radical of 3- to 6-membered non-aromatic ring system having ringcarbon atoms and 1 to 3 ring heteroatoms; 4- to 6-membered heterocyclylis alternative, which is a radical of 4- to 6-membered non-aromatic ringsystem having ring carbon atoms and 1 to 3 ring heteroatoms; 5- to6-membered heterocyclyl is more alternative, which is a radical of 5- to6-membered non-aromatic ring system having ring carbon atoms and 1 to 3ring heteroatoms; 5-membered heterocyclyl is more alternative, which isa radical of 5-membered non-aromatic ring system having ring carbonatoms and 1 to 3 ring heteroatoms; 6-membered heterocyclyl is morealternative, which is a radical of 6-membered non-aromatic ring systemhaving ring carbon atoms and 1 to 3 ring heteroatoms. The heterocyclylalso includes a ring system wherein the heterocyclyl described above isfused with one or more cycloalkyl groups, wherein the point ofattachment is on the heterocyclyl ring, or the heterocyclyl describedabove is fused with one or more aryl or heteroaryl groups, wherein thepoint of attachment is on the heterocyclyl ring; and in such cases, thenumber of ring members continues to represent the number of ring membersin the heterocyclyl ring system. The heterocyclyl further comprises theheterocyclyl described above, in which the substituents on anynon-adjacent carbon or nitrogen atoms are connected to form a bridgering, together forming a polycyclic heteroalkane sharing two or morecarbon or nitrogen atoms. The heterocyclyl further comprises theheterocyclyl described above, in which the substituents on the samecarbon atom are connected to form a ring, together forming a polycyclicheteroalkane sharing one carbon atom. Exemplary 3-membered heterocyclylgroups containing one heteroatom include, but are not limited to,aziridinyl, oxiranyl and thiorenyl. Exemplary 4-membered heterocyclylgroups containing one heteroatom include, but are not limited to,azetidinyl, oxetanyl and thietanyl. Exemplary 5-membered heterocyclylgroups containing one heteroatom include, but are not limited to,tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothienyl,pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2,5-dione. Exemplary5-membered heterocyclyl groups containing two heteroatoms include, butare not limited to, pyrazolidyl, dioxolanyl, oxasulfuranyl,disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclylgroups containing three heteroatoms include, but are not limited to,triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-memberedheterocyclyl groups containing one heteroatom include, but are notlimited to, piperidyl, tetrahydropyranyl, dihydropyridyl and thianyl.Exemplary 6-membered heterocyclyl groups containing two heteroatomsinclude, but are not limited to, piperazinyl, morpholinyl, dithianyl anddioxanyl. Exemplary 6-membered heterocyclyl groups containing threeheteroatoms include, but are not limited to, triazinanyl. Exemplary7-membered heterocyclyl groups containing one heteroatom include, butare not limited to, azepanyl, oxepanyl and thiepanyl. Exemplary5-membered heterocyclyl groups fused with a C₆ aryl (also referred as5,6-bicyclic heterocyclyl herein) include, but are not limited to,indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl,benzoxazolinonyl, etc. Exemplary 6-membered heterocyclyl groups fusedwith a C₆ aryl (also referred as 6,6-bicyclic heterocyclyl herein)include, but are not limited to, tetrahydroquinolinyl,tetrahydroisoquinolinyl, etc. The heterocyclyl further includes theheterocyclyl described above sharing one or two atoms with a cycloalkyl,heterocyclyl, aryl or heteroaryl to form a bridged or spiro ring, aslong as the valence permits, where the shared atom may be carbon ornitrogen atoms. The heterocyclyl further includes the heterocyclyldescribed above, which optionally can be substituted with one or moresubstituents, e.g., with 1 to 5 substituents, 1 to 3 substituents or 1substituent.

“C₆₋₁₀ aryl” refers to a radical of monocyclic or polycyclic (e.g.,bicyclic) 4n+2 aromatic ring system having 6-10 ring carbon atoms andzero heteroatoms (e.g., having 6 or 10 shared π electrons in a cyclicarray). In some embodiments, the aryl group has six ring carbon atoms(“C₆ aryl”; for example, phenyl). In some embodiments, the aryl grouphas ten ring carbon atoms (“C₁₀ aryl”; for example, naphthyl, e.g.,1-naphthyl and 2-naphthyl). The aryl group also includes a ring systemin which the aryl ring described above is fused with one or morecycloalkyl or heterocyclyl groups, and the point of attachment is on thearyl ring, in which case the number of carbon atoms continues torepresent the number of carbon atoms in the aryl ring system. The arylcan be substituted with one or more substituents, for example, with 1 to5 substituents, 1 to 3 substituents or 1 substituent.

“5- to 14-membered heteroaryl” refers to a radical of 5- to 14-memberedmonocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6, 10 or14 shared 11 electrons in a cyclic array) having ring carbon atoms and1-4 ring heteroatoms, wherein each heteroatom is independently selectedfrom nitrogen, oxygen and sulfur. In the heteroaryl group containing oneor more nitrogen atoms, the point of attachment can be a carbon ornitrogen atom as long as the valence permits. heteroaryl bicyclicsystems may include one or more heteroatoms in one or two rings.heteroaryl also includes ring systems wherein the heteroaryl ringdescribed above is fused with one or more cycloalkyl or heterocyclylgroups, and the point of attachment is on the heteroaryl ring. In suchcase, the number the carbon atoms continues to represent the number ofcarbon atoms in the heteroaryl ring system. In some embodiments, 5- to10-membered heteroaryl groups are alternative, which are radicals of 5-to 10-membered monocyclic or bicyclic 4n+2 aromatic ring systems havingring carbon atoms and 1-4 ring heteroatoms. In other embodiments, 5- to6-membered heteroaryl groups are yet alternative, which are radicals of5- to 6-membered monocyclic or bicyclic 4n+2 aromatic ring systemshaving ring carbon atoms and 1-4 ring heteroatoms. Exemplary 5-memberedheteroaryl groups containing one heteroatom include, but are not limitedto, pyrrolyl, furyl and thienyl. Exemplary 5-membered heteroaryl groupscontaining two heteroatoms include, but are not limited to, imidazolyl,pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary5-membered heteroaryl groups containing three heteroatoms include, butare not limited to, triazolyl, oxadiazolyl (such as, 1,2,4-oxadiazolyl),and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing fourheteroatoms include, but are not limited to, tetrazolyl. Exemplary6-membered heteroaryl groups containing one heteroatom include, but arenot limited to, pyridyl or pyridonyl. Exemplary 6-membered heteroarylgroups containing two heteroatoms include, but are not limited to,pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroarylgroups containing three or four heteroatoms include, but are not limitedto, triazinyl and tetrazinyl, respectively. Exemplary 7-memberedheteroaryl groups containing one heteroatom include, but are not limitedto, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroarylgroups include, but are not limited to, indolyl, isoindolyl, indazolyl,benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl,benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl,benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl,indolizinyl and purinyl. Exemplary 6,6-bicyclic heteroaryl groupsinclude, but are not limited to, naphthyridinyl, pteridinyl, quinolyl,isoquinolyl, cinnolinyl, quinoxalinyl, phthalazinyl and quinazolinyl.The heteroaryl can be substituted with one or more substituents, forexample, with 1 to 5 substituents, 1 to 3 substituents or 1 substituent.

“Hydroxyalkyl” refers to an alkyl group that is substituted with one ormore hydroxyl groups.

“Alkoxy” refers to an oxyether form of a linear or branched-chain alkylgroup, i.e., an —O-alkyl group. Similarly, “methoxy” refers to —O—CH₃.

“Optionally substituted with” means that it can be substituted with thespecified substituents or unsubstituted.

The divalent groups formed by removing another hydrogen from the groupsdefined above such as alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,aryl and heteroaryl are collectively referred to as “-ylene”.Ring-forming groups such as cycloalkyl, heterocyclyl, aryl andheteroaryl are collectively referred to as “cyclic groups”.

alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroarylas defined herein are optionally substituted groups.

Exemplary substituents on carbon atoms include, but are not limited to,halogen, —CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(aa), —ON(R^(bb))₂,—N(R^(bb))₂, —N(R^(bb))₃ ⁺X⁻, —N(OR^(cc))R^(bb), —SH, —SR^(aa),—SSR^(cc), —C(═O)R^(aa), —CO₂H, —CHO, —C(OR^(cc))₂, —CO₂R^(aa),—OC(═O)R^(aa), —OCO₂R^(aa), —C(═O)N(R^(bb))₂, —OC(═O)N(R^(bb))₂,—NR^(bb)C(═O)R^(aa), —NR^(bb)CO₂R^(aa), —NR^(bb)C(═O)N(R^(bb))₂,—C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa), —OC(═NR^(bb))R^(aa),—OC(═NR^(bb))OR^(aa), —C(═NR^(bb))N(R^(bb))₂, —OC(═NR^(bb))N(R^(bb))₂,—NR^(bb)C(═NR^(bb))N(R^(bb))₂, —C(═O)NR^(bb)SO₂R^(aa),—NR^(bb)SO₂R^(aa), —SO₂N(R^(bb))₂, —SO₂R^(aa), —SO₂OR^(aa), —OSO₂R^(aa),—S(═O)R^(aa), —OS(═O)R^(aa), —Si(R^(aa))₃, —OSi(R^(aa))₃,—C(═S)N(R^(bb))₂, —C(═O)SR^(aa), —C(═S)SR^(aa), —SC(═S)SR^(aa),—SC(═O)SR^(aa), —OC(═O)SR^(aa), —SC(═O)OR^(aa), —SC(═O)R^(aa),—P(═O)₂R^(aa), —OP(═O)₂R^(aa), —P(═O)(R^(aa))₂, —OP(═O)(R^(aa))₂,—OP(═O)(OR^(cc))₂, —P(═O)₂N(R^(bb))₂, —OP(═O)₂N(R^(bb))₂,—P(═O)(NR^(bb))₂, —OP(═O)(NR^(bb))₂, —NR^(bb)P(═O)(OR″)₂,—NR^(bb)P(═O)(NR^(bb))₂, —P(R^(cc))₂, —P(R^(cc))₃, —OP(R^(cc))₂,—OP(R^(cc))₃, —B(R^(aa))₂, —B(OR^(cc))₂, —BR^(aa)(OR^(cc)), alkyl,haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl andheteroaryl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl and heteroaryl is independently substituted with 0,1, 2, 3, 4 or 5 R^(dd) groups;

-   -   or two geminal hydrogen on a carbon atom are replaced with ═O,        ═S, ═NN(R^(bb))₂, ═NNR^(bb)C(═O)R^(aa), ═NNR^(bb)C(═O)OR^(aa),        ═NNR^(bb)S(═O)₂R^(aa), ═NR^(bb) or ═NOR^(cc) groups;    -   each of the R^(aa) is independently selected from alkyl,        haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and        heteroaryl, or two of the R^(aa) groups are combined to form a        heterocyclyl or heteroaryl ring, wherein each of the alkyl,        alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl        is independently substituted with 0, 1, 2, 3, 4 or 5 R^(dd)        groups;    -   each of the R^(bb) is independently selected from hydrogen, —OH,        —OR^(aa), —N(R^(cc))₂, —CN, —C(═O)R^(aa), —C(═O)N(R^(cc))₂,        —CO₂R^(aa), —SO₂R^(aa), —C(═NR^(cc))OR^(aa),        —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc), —SO₂OR^(cc),        —SOR^(a), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc),        —P(═O)₂R^(aa), —P(═O)(R^(aa))₂, —P(═O)₂N(R^(cc))₂,        —P(═O)(NR^(cc))₂, alkyl, haloalkyl, alkenyl, alkynyl,        cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R^(bb)        groups are combined to form a heterocyclyl or a heteroaryl ring,        wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl,        heterocyclyl, aryl and heteroaryl is independently substituted        with 0, 1, 2, 3, 4 or 5 R^(dd) groups;    -   each of the R^(cc) is independently selected from hydrogen,        alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,        aryl and heteroaryl, or two R^(cc) groups are combined to form a        heterocyclyl or a heteroaryl ring, wherein each of the alkyl,        alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl        is independently substituted with 0, 1, 2, 3, 4 or 5 R^(dd)        groups;    -   each of the R^(dd) is independently selected from halogen, —CN,        —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(ee), —ON(R^(ff))₂,        —N(R^(ff))₂, —N(R^(ff))₃ ⁺X⁻, —N(OR^(ee))R, —SH, —SR^(ee),        —SSR^(ee), —C(═O)R^(ee), —CO₂H, —CO₂R^(ee), —OC(═O)R^(ee),        —OCO₂R^(ee), —C(═O)N(R^(ff))₂, —OC(═O)N(R^(ff))₂,        —NR^(ff)C(═O)R^(ee), —NR^(ff)CO₂R^(ee), —NR^(ff)C(═O)N(R_(f))₂,        —C(═NR^(ff))OR^(ee), —OC(═NR^(ff))R^(ee), —OC(═NR^(ff))OR^(ee),        —C(═NR^(ff))N(R^(ff))₂, —OC(═NR^(ff))N(R^(ff))₂,        —NR^(ff)C(═NR^(ff))N(R_(f))₂, —NR^(ff)SO₂R^(ee), —SO₂N(R^(ff))₂,        —SO₂R^(ee), —SO₂OR^(ee), —OSO₂R^(ee), —S(═O)R^(ee),        —Si(R^(ee))₃, —OSi(R^(ee))₃, —C(═S)N(R^(ff))₂, —C(═O)SR^(ee),        —C(═S)SR^(ee), —SC(═S)SR^(ee), —P(═O)₂R^(ee), —P(═O)(R^(ee))₂,        —OP(═O)(R^(ee))₂, —OP(═O)(OR^(ee))₂, alkyl, haloalkyl, alkenyl,        alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein        each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,        aryl and heteroaryl is independently substituted with 0, 1, 2,        3, 4 or 5 R^(gg) groups, or two geminal R^(dd) substituents can        be combined to form ═O or ═S;    -   each of the R^(ee) is independently selected from alkyl,        haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and        heteroaryl, wherein each of the alkyl, alkenyl, alkynyl,        cycloalkyl, heterocyclyl, aryl and heteroaryl is independently        substituted with 0, 1, 2, 3, 4 or 5 R^(gg) groups;    -   each of the R^(f) is independently selected from hydrogen,        alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,        aryl and heteroaryl, or two R^(f) groups are combined to form a        heterocyclyl or a heteroaryl ring, wherein each of the alkyl,        alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl        is independently substituted with 0, 1, 2, 3, 4 or 5 R^(gg)        groups;    -   each of the R^(gg) is independently selected from halogen, —CN,        —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OC₁₋₆ alkyl, —ON(C₁₋₆ alkyl)₂,        —N(C₁₋₆ alkyl)₂, —N(C₁₋₆ alkyl)₃ ⁺X⁻, —NH(C₁₋₆ alkyl)₂ ⁺X⁻,        —NH₂(C₁₋₆ alkyl)⁺X⁻, —NH₃ ⁺X⁻, —N(OC₁₋₆ alkyl)(C₁₋₆ alkyl),        —N(OH)(C₁₋₆ alkyl), —NH(OH), —SH, —SC₁₋₆ alkyl, —SS(C₁₋₆ alkyl),        —C(═O)(C₁₋₆ alkyl), —CO₂H, —CO₂(C₁₋₆ alkyl), —OC(═O)(C₁₋₆        alkyl), —OCO₂(C₁₋₆ alkyl), —C(═O)NH₂, —C(═O)N(C₁₋₆ alkyl)₂,        —OC(═O)NH(C₁₋₆ alkyl), —NHC(═O)(C₁₋₆ alkyl), —N(C₁₋₆        alkyl)C(═O)(C₁₋₆ alkyl), —NHCO₂(C₁₋₆ alkyl), —NHC(═O)N(C₁₋₆        alkyl)₂, —NHC(═O)NH(C₁₋₆ alkyl), —NHC(═O)NH₂, —C(═NH)O(C₁₋₆        alkyl), —OC(═NH)(C₁₋₆ alkyl), —OC(═NH)OC₁₋₆ alkyl, —C(═NH)N(C₁₋₆        alkyl)₂, —C(═NH)NH(C₁₋₆ alkyl), —C(═NH)NH₂, —OC(═NH)N(C₁₋₆        alkyl)₂, —OC(NH)NH(C₁₋₆ alkyl), —OC(NH)NH₂, —NHC(NH)N(C₁₋₆        alkyl)₂, —NHC(═NH)NH₂, —NHSO₂(C₁₋₆ alkyl), —SO₂N(C₁₋₆ alkyl)₂,        —SO₂NH(C₁₋₆ alkyl), —SO₂NH₂, —SO₂C₁₋₆ alkyl, —SO₂OC₁₋₆ alkyl,        —OSO₂C₁₋₆ alkyl, —SOC₁₋₆ alkyl, —Si(C₁₋₆ alkyl)₃, —OSi(C₁₋₆        alkyl)₃, —C(═S)N(C₁₋₆ alkyl)₂, C(═S)NH(C₁₋₆ alkyl), C(═S)NH₂,        —C(═O)S(C₁₋₆ alkyl), —C(═S)SC₁₋₆ alkyl, —SC(═S)SC₁₋₆ alkyl,        —P(═O)₂(C₁₋₆ alkyl), —P(═O)(C₁₋₆ alkyl)₂, —OP(═O)(C₁₋₆ alkyl)₂,        —OP(═O)(OC₁₋₆ alkyl)₂, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂-C₆        alkenyl, C₂-C₆ alkynyl, C₃-C₇ cycloalkyl, C₆-C₁₀ aryl, C₃-C₇        heterocyclyl, C₅-C₁₀ heteroaryl; or two geminal R₉₉ substituents        may combine to form ═O or ═S; wherein X⁻ is a counter-ion.

Exemplary substituents on nitrogen atoms include, but are not limitedto, hydrogen, —OH, —OR^(aa), —N(R^(cc))₂, —CN, —C(═O)R^(aa),—C(═O)N(R^(cc))₂, —CO₂R^(aa), —SO₂R^(aa), —C(═NR^(bb))R^(aa),—C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc),—SO₂OR^(cc), —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc),—P(═O)₂R^(aa), —P(═O)(R^(aa))₂, —P(═O)₂N(R^(cc))₂, —P(═O)(NR^(cc))₂,alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl andheteroaryl, or two R^(cc) groups attached to a nitrogen atom combine toform a heterocyclyl or a heteroaryl ring, wherein each of the alkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl isindependently substituted with 0, 1, 2, 3, 4 or 5 R^(dd) groups, andwherein R^(aa), R^(bb), R^(cc) and R^(dd) are as described herein.

“Nucleic acids” refers to single- or double-stranded deoxyribonucleicacid (DNA) or ribonucleic acid (RNA) molecules and their heterozygousmolecules. Examples of nucleic acid molecules include, but are notlimited to, messenger RNA (mRNA), microRNA (miRNA), small interferingRNA (siRNA), self-amplified RNA (saRNA), and antisense oligonucleotides(ASO), etc. Nucleic acids may be further chemically modified, and thechemical modifier selected from one of, or a combination of:pseudouridine, N1-methyl-pseudouridine, 5-methoxyuridine, and5-methylcytosine. mRNA molecules contain protein coding regions and mayfurther contain expression regulatory sequences.

Typical expression regulatory sequences include, but are not limited to,5′ cap, 5′ untranslated region (5′ UTR), 3′ untranslated region (3′UTR), polyadenylate sequence (PolyA), miRNA binding sites.

“Cationic lipids” refers to lipid molecules that is capable of beingpositively charged at physiological pH conditions. In some embodiments,the cationic lipid is an amino lipid.

“Neutral lipids” refers to lipid molecules that is not charged at aparticular pH, such as physiological pH conditions. Examples of neutrallipids include, but are not limited to

-   1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC),-   1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC),-   1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC),-   1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC),-   1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC),-   1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE),-   1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine (DMPE),-   1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (POPE), and-   1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE).

“Structure lipids” refers to lipids that enhance the stability ofnanoparticles by filling the gaps between lipids, commonly such assteroids. The steroid is a compound having aperhydrocyclopentanophenanthrene carbon framework. In an alternativeembodiment, the steroid is cholesterol, sitosterol, coprosterol,fucosterol, brassicasterol, ergosterol, tomatine, ursolic acid,α-tocopherol, stigmasterol, avenasterol, ergocalciferol or campesterol.

“Polymer lipids” refers to molecules containing a polymer moiety and alipid moiety.

In some embodiments, the polymer lipid is a polyethylene glycol (PEG)lipid. Other lipids that can reduce aggregation, such as products ofcompounds having uncharged, hydrophilic, space-barrier moieties coupledwith lipid may also be used.

“Lipid nanoparticles” refers to particles containing lipid components ofnanoscale size.

“Biodegradable groups” refers to functional groups that containbiodegradable bonds, such as esters, disulfide bonds and amides, etc.Biodegradation may affect the process of removing compounds from thebody. The biodegradable groups of the present disclosure are orientedfrom the head to the tail in ionizable lipid molecules.

Other Terminology

The term “treating” as used herein relates to reversing, alleviating orinhibiting the progression or prevention of the disorders or conditionsto which the term applies, or of one or more symptoms of such disordersor conditions. The noun “treatment” as used herein relates to the actionof treating, which is a verb, and the latter is as just defined.

The term “pharmaceutically acceptable salt” as used herein refers tothose carboxylate and amino acid addition salts of the compounds of thepresent disclosure, which are suitable for the contact with patients'tissues within a reliable medical judgment, and do not produceinappropriate toxicity, irritation, allergy, etc. They are commensuratewith a reasonable benefit/risk ratio, and are effective for theirintended use. The term includes, if possible, the zwitterionic form ofthe compounds of the disclosure.

The pharmaceutically acceptable base addition salts are formed withmetals or amines, such as alkali metal and alkaline earth metalhydroxides or organic amines. Examples of the metals used as cationsinclude sodium, potassium, magnesium, calcium, etc. Examples of suitableamines are N,N′-dibenzylethylenediamine, chloroprocaine, choline,diethanolamine, ethylenediamine, N-methylglucamine and procaine.

The base addition salt of the acidic compound can be prepared bycontacting the free acid form with a sufficient amount of the requiredbase to form a salt in a conventional manner. The free acid can beregenerated by contacting the salt form with an acid in a conventionalmanner and then isolating the free acid. The free acid forms aresomewhat different from their respective salt forms in their physicalproperties, such as solubility in polar solvents. But for the purposesof the present disclosure, the salts are still equivalent to theirrespective free acids.

The salts can be prepared from the inorganic acids, which includesulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates,phosphates, monohydrogen phosphates, dihydrogen phosphates,metaphosphates, pyrophosphates, chlorides, bromides and iodides.Examples of the acids include hydrochloric acid, nitric acid, sulfuricacid, hydrobromic acid, hydroiodic acid, phosphoric acid, etc. Therepresentative salts include hydrobromide, hydrochloride, sulfate,bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate,stearate, laurate, borate, benzoate, lactate, phosphate, tosylate,citrate, maleate, fumarate, succinate, tartrate, naphthalate,methanesulfonate, glucoheptanate, lactobionate, lauryl sulfonate,isethionate, etc. The salts can also be prepared from the organic acids,which include aliphatic monocarboxylic and dicarboxylic acids,phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioicacid, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Therepresentative salts include acetate, propionate, octanoate,isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate,maleate, mandelate, benzoate, chlorobenzoate, methyl benzoate,dinitrobenzoate, naphthoate, besylate, tosylate, phenylacetate, citrate,lactate, maleate, tartrate, methanesulfonate, etc. The pharmaceuticallyacceptable salts can include cations based on alkali metals and alkalineearth metals, such as sodium, lithium, potassium, calcium, magnesium,etc., as well as non-toxic ammonium, quaternary ammonium, and aminecations including, but not limited to, ammonium, tetramethylammonium,tetraethylammonium, methylamine, dimethylamine, trimethylamine,triethylamine, ethylamine, etc. Salts of amino acids are also included,such as arginine salts, gluconates, galacturonates, etc. (for example,see Berge S. M. et al., “Pharmaceutical Salts,” J. Pharm. Sci., 1977;66: 1-19 for reference).

“Subjects” to which administration is contemplated include, but are notlimited to, humans (e.g., males or females of any age group, e.g.,paediatric subjects (e.g., infants, children, adolescents) or adultsubjects (e.g., young adults, middle-aged adults or older adults) and/ornon-human animals, such as mammals, e.g., primates (e.g., cynomolgusmonkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents,cats and/or dogs. In some embodiments, the subject is a human. In someembodiments, the subject is a non-human animal. The terms “human”,“patient” and “subject” can be used interchangeably herein.

“Disease”, “disorder”, and “condition” can be used interchangeablyherein.

Unless otherwise indicated, the term “treatment” as used herein includesthe effect on a subject who is suffering from a particular disease,disorder, or condition, which reduces the severity of the disease,disorder, or condition, or delays or slows the progression of thedisease, disorder or condition (“therapeutic treatment”). The term alsoincludes the effect that occurs before the subject begins to suffer froma specific disease, disorder or condition (“prophylactic treatment”).

Generally, the “effective amount” of a pharmaceutical composition refersto an amount sufficient to elicit a target biological response. Asunderstood by those skilled in the art, the effective amount of thepharmaceutical composition of the disclosure can vary depending on thefollowing factors, such as the desired biological endpoint, thepharmacokinetics of the pharmaceutical composition, the diseases beingtreated, the mode of administration, and the age, health status andsymptoms of the subjects. The effective amount includes therapeuticallyeffective amount and prophylactically effective amount.

Unless otherwise indicated, the “therapeutically effective amount” ofthe pharmaceutical composition as used herein is an amount sufficient toprovide therapeutic benefits in the course of treating a disease,disorder or condition, or to delay or minimize one or more symptomsassociated with the disease, disorder or condition. The therapeuticallyeffective amount of a pharmaceutical composition refers to the amount ofthe therapeutic agent that, when used alone or in combination with othertherapies, provides a therapeutic benefit in the treatment of a disease,disorder or condition. The term “therapeutically effective amount” caninclude an amount that improves the overall treatment, reduces or avoidsthe symptoms or causes of the disease or condition, or enhances thetherapeutic effect of other therapeutic agents.

Unless otherwise indicated, the “prophylactically effective amount” ofthe pharmaceutical composition as used herein is an amount sufficient toprevent a disease, disorder or condition, or an amount sufficient toprevent one or more symptoms associated with a disease, disorder orcondition, or an amount sufficient to prevent the recurrence of adisease, disorder or condition. The prophylactically effective amount ofa pharmaceutical composition refers to the amount of a therapeutic agentthat, when used alone or in combination with other agents, provides aprophylactic benefit in the prevention of a disease, disorder orcondition. The term “prophylactically effective amount” can include anamount that improves the overall prevention, or an amount that enhancesthe prophylactic effect of other preventive agents.

“Combination” and related terms refer to the simultaneous or sequentialadministration of the pharmaceutical compositions of the presentdisclosure and other therapeutic agents. For example, the pharmaceuticalcompositions of the present disclosure can be administeredsimultaneously or sequentially in separate unit dosage with othertherapeutic agents, or simultaneously in a single unit dosage with othertherapeutic agents.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, “compounds of the present disclosure” refers to thefollowing compounds of formula (IV), formula (V), formula (VI), formula(VII), and the like, pharmaceutically acceptable salts, isotopicvariants, tautomers or stereoisomers thereof.

In the present disclosure, compounds are named using standardnomenclature. For compounds having an asymmetric center, it should beunderstood, unless otherwise stated, that all optical isomers andmixtures thereof are included. Furthermore, unless otherwise specified,all isomer compounds and carbon-carbon double bonds included in thepresent disclosure may occur in the form of Z and E. Compounds whichexist in different tautomeric forms, one of which is not limited to anyparticular tautomer, but is intended to cover all tautomeric forms.

In one embodiment, the present disclosure relates to a compound offormula (IV), or a pharmaceutically acceptable salt, isotopic variant,tautomer or stereoisomer thereof:

-   -   wherein,    -   M₁ and M₂ are independently selected from —C(O)O—, —O—,        —SC(O)O—, —OC(O)NR_(a)—, —NR_(a)C(O)NR_(a)—, —OC(O)S—, —OC(O)O—,        —NR_(a)C(O)O—, —OC(O)—, —SC(O)—, —C(O)S—, —NR_(a)—,        —C(O)NR_(a)—, —NR_(a)C(O)—, —NR_(a)C(O)S—, —SC(O)NR_(a)—,        —C(O)—, —OC(S)—, —C(S)O—, —OC(S)NR_(a)—, —NR_(a)C(S)O—, —S—S—        and —S(O)₀₋₂—;    -   Q is selected from a chemical bond, —C(O)O—, —O—, —SC(O)O—,        —OC(O)NR_(b)—, —NR_(b)C(O)NR_(b)—, —OC(O)S—, —OC(O)O—,        —NR_(b)C(O)O—, —OC(O)—, —SC(O)—, —C(O)S—, —NR_(b)—,        —C(O)NR_(b)—, —NR_(b)C(O)—, —NR_(b)C(O)S—, —SC(O)NR_(b)—,        —C(O)—, —OC(S)—, —C(S)O—, —OC(S)NR_(b)—, —NR_(b)C(S)O—, —S—S—,        —S(O)₀₋₂—, phenylene and pyridylidene, wherein, the phenylene or        pyridylidene is optionally substituted with one or more R*;    -   G₅ is a chemical bond or C₁₋₈ alkylene, which is optionally        substituted with one or more R**;    -   G_(6a) and G_(6b) are independently a chemical bond or C₁₋₇        alkylene, which is optionally substituted with one or more R**;    -   G_(6a) and G_(6b) have a total length of 0, 1, 2, 3, 4, 5, 6 or        7 carbon atoms;    -   R₉, R₁₀ and R** are independently H, C₁₋₈ alkyl, -L_(c)-OR_(c),        -L_(c)-SR_(c) or -L_(c)-NR_(c)R′_(c);    -   G₁, G₂, G₃ and G₄ are independently a chemical bond, C₁₋₁₃        alkylene, C₂₋₁₃ alkenylene or C₂₋₁₃ alkynylene, which is        optionally substituted with one or more R^(s);    -   G₁ and G₂ have a total length of 3, 4, 5, 6, 7, 8, 9, 10, 11, 12        or 13 carbon atoms;    -   G₃ and G₄ have a total length of 3, 4, 5, 6, 7, 8, 9, 10, 11, 12        or 13 carbon atoms;    -   R₃ and R₄ are independently H, C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl,        C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, 3- to 14-membered cycloalkyl, 3-        to 14-membered heterocyclyl, C₆₋₁₀ aryl or 5- to 14-membered        heteroaryl, which is optionally substituted with one or more R*:    -   or, R₃ and R₄ are taken together with the N atom to which they        are attached to form 3- to 14-membered heterocyclyl, which is        optionally substituted with one or more R*;    -   or, R₄ and R₉ are taken together with the atoms to which they        are attached to form 3- to 14-membered heterocyclyl or 5- to        14-membered heteroaryl, which is optionally substituted with one        or more R*;    -   R* is independently H, halogen, cyano, C₁₋₁₀ alkyl, C₁₋₁₀        haloalkyl, -L_(b)-OR_(b), -L_(b)-SR_(b) or -L_(b)-NR_(b)R′_(b);    -   R₅, R₆, R₇ and R₈ are independently C₁₋₈ alkyl, which is        optionally substituted with one or more R*;    -   R₁ and R₂ are independently C₄₋₂₀ alkyl, C₄₋₂₀ alkenyl or C₄₋₂₀        alkynyl, which is optionally substituted with one or more R, and        wherein one or more methylene units are optionally and        independently replaced with —NR″—;    -   R^(s) is independently H, C₁₋₁₄ alkyl, -L_(d)-OR_(d),        -L_(d)-SR_(d) or -L_(d)-NR_(d)R′_(d);    -   R is independently H, C₁₋₂₀ alkyl, -L_(a)-OR_(a), -L_(a)-SR_(a)        or -L_(a)-NR_(a)R′_(a);    -   R″ is independently H or C₁₋₂₀ alkyl;    -   L_(a) and L_(e) are independently a chemical bond or C₁₋₂₀        alkylene;    -   L_(b) and L_(f) are independently a chemical bond or C₁₋₁₀        alkylene;    -   L_(c) is independently a chemical bond or C₁₋₈ alkylene;    -   L_(d) is independently a chemical bond or C₁₋₁₄ alkylene;    -   R_(a) and R′_(a) are independently selected from H, C₁₋₂₀ alkyl,        3- to 14-membered cycloalkyl, and 3- to 14-membered        heterocyclyl, which are optionally substituted with one or more        of the following substituents: H, C₁₋₂₀ alkyl, -L_(e)-OR_(e),        -L_(e)-SR_(e) and -L_(e)-NR_(e)R′_(e);    -   R_(b) and R′_(b) are independently selected from H, C₁₋₁₀ alkyl,        3- to 14-membered cycloalkyl, and 3- to 14-membered        heterocyclyl, which are optionally substituted with one or more        of the following substituents: H, C₁₋₁₀ alkyl, -L_(f)-OR_(f),        -L_(f)-SR_(f) and -L_(f)-NR_(f)R′_(f);    -   R_(c) and R′_(c) are independently H or C₁₋₈ alkyl;    -   R_(d) and R′_(d) are independently H or C₁₋₁₄ alkyl;    -   R_(e) and R′_(e) are independently H or C₁₋₂₀ alkyl;    -   R_(f) and R′_(f) are independently H or C₁₋₁₀ alkyl.

M₁ and M₂

In one embodiment, M₁ is —C(O)O—; in another embodiment, M₁ is —O—; inanother embodiment, M₁ is —SC(O)O—; in another embodiment, M₁ is—OC(O)NR_(a)—; in another embodiment, M₁ is —NR_(a)C(O)NR_(a)—; inanother embodiment, M₁ is —OC(O)S—; in another embodiment, M₁ is—OC(O)O—; in another embodiment, M₁ is —NR_(a)C(O)O—; in anotherembodiment, M₁ is —OC(O)—; in another embodiment, M₁ is —SC(O)—; inanother embodiment, M₁ is —C(O)S—; in another embodiment, M₁ is—NR_(a)—; in another embodiment, M₁ is —C(O)NR_(a)—; in anotherembodiment, M₁ is —NR_(a)C(O)—; in another embodiment, M₁ is—NR_(a)C(O)S—; in another embodiment, M₁ is —SC(O)NR_(a)—; in anotherembodiment, M₁ is —C(O)—; in another embodiment, M₁ is —OC(S)—; inanother embodiment, M₁ is —C(S)O—; in another embodiment, M₁ is—OC(S)NR_(a)—; in another embodiment, M₁ is —NR_(a)C(S)O—; in anotherembodiment, M₁ is —S—S—; in another embodiment, M₁ is —S(O)₀₋₂—.

In one embodiment, M₂ is —C(O)O—; in another embodiment, M₂ is —O—; inanother embodiment, M₂ is —SC(O)O—; in another embodiment, M₂ is—OC(O)NR_(a)—; in another embodiment, M₂ is —NR_(a)C(O)NR_(a)—; inanother embodiment, M₂ is —OC(O)S—; in another embodiment, M₂ is—OC(O)O—; in another embodiment, M₂ is —NR_(a)C(O)O—; in anotherembodiment, M₂ is —OC(O)—; in another embodiment, M₂ is —SC(O)—; inanother embodiment, M₂ is —C(O)S—; in another embodiment, M₂ is—NR_(a)—; in another embodiment, M₂ is —C(O)NR_(a)—; in anotherembodiment, M₂ is —NR_(a)C(O)—; in another embodiment, M₂ is—NR_(a)C(O)S—; in another embodiment, M₂ is —SC(O)NR_(a)—; in anotherembodiment, M₂ is —C(O)—; in another embodiment, M₂ is —OC(S)—; inanother embodiment, M₂ is —C(S)O—; in another embodiment, M₂ is—OC(S)NR_(a)—; in another embodiment, M₂ is —NR_(a)C(S)O—; in anotherembodiment, M₂ is —S—S—; in another embodiment, M₂ is —S(O)₀₋₂—.

In a more specific embodiment, M₁ and M₂ are independently selected from—C(O)O—, —SC(O)O—, —OC(O)NR_(a)—, —NR_(a)C(O)NR_(a)—, —OC(O)S—,—OC(O)O—, —NR_(a)C(O)O—, —C(O)S—, —C(O)NR_(a)—, —NR_(a)C(O)S—,—SC(O)NR_(a)—, —C(S)O—, —OC(S)NR_(a)— and —NR_(a)C(S)O—; in another morespecific embodiment, M₁ and M₂ are independently —C(O)O—, —C(O)S—,—C(O)NR_(a)—, or —C(S)O—; in another more specific embodiment, M₁ and M₂are independently —C(O)O—, —C(O)S— or —C(O)NR_(a)—.

Q

In one embodiment, Q is a chemical bond; in another embodiment, Q is—C(O)O—; in another embodiment, Q is —O—; in another embodiment, Q is—SC(O)O—; in another embodiment, Q is —OC(O)NR_(b)—; in anotherembodiment, Q is —NR_(b)C(O)NR_(b)—; in another embodiment, Q is—OC(O)S—; in another embodiment, Q is —OC(O)O—; in another embodiment, Qis —NR_(b)C(O)O—; in another embodiment, Q is —OC(O)—; in anotherembodiment, Q is —SC(O)—; in another embodiment, Q is —C(O)S—; inanother embodiment, Q is —NR_(b)—; in another embodiment, Q is—C(O)NR_(b)—; in another embodiment, Q is —NR_(b)C(O)—; in anotherembodiment, Q is —NR_(b)C(O)S—; in another embodiment, Q is—SC(O)NR_(b)—; in another embodiment, Q is —C(O)—; in anotherembodiment, Q is —OC(S)—; in another embodiment, Q is —C(S)O—; inanother embodiment, Q is —OC(S)NR_(b)—; in another embodiment, Q is—NR_(b)C(S)O—; in another embodiment, Q is —S—S—; in another embodiment,Q is —S(O)₀₋₂—; in another embodiment, Q is phenylene; in anotherembodiment, Q is pyridylidene; in another embodiment, the phenylene orpyridylidene is optionally substituted with one or more R*.

In a more specific embodiment, Q is selected from a chemical bond,—C(O)O—, —O—, —SC(O)O—, —OC(O)NR_(b)—, —NR_(b)C(O)NR_(b)—, —OC(O)S—,—OC(O)O—, —NR_(b)C(O)O—, —OC(O)—, —SC(O)—, —C(O)S—, —NR_(b)—,—C(O)NR_(b)—, —NR_(b)C(O)—, —NR_(b)C(O)S—, —SC(O)NR_(b)—, —C(O)—,—OC(S)—, —C(S)O—, —OC(S)NR_(b)—, —NR_(b)C(S)O—, —S—S—, and —S(O)₀₋₂—; inanother more specific embodiment, Q is selected from —C(O)O—, —O—,—SC(O)O—, —OC(O)NH—, —NHC(O)NH—, —OC(O)S—, —OC(O)O—, —NHC(O)O—, —OC(O)—,—SC(O)—, —C(O)S—, —NH—, —C(O)NH—, —NHC(O)—, —NHC(O)S—, —SC(O)NH—,—C(O)—, —OC(S)—, —C(S)O—, —OC(S)NH— and —NHC(S)O—; in another morespecific embodiment, Q is selected from —C(O)O—, —O—, —SC(O)O—,—OC(O)NH—, —NHC(O)NH—, —OC(O)S—, —OC(O)O— and —NHC(O)O—; in another morespecific embodiment, Q is —C(O)O—.

G₅

In one embodiment, G₅ is a chemical bond; in another embodiment, G₅ isC₁₋₈ alkylene; in another embodiment, G₅ is optionally substituted withone or more R**.

G_(6a) and G₆b

In one embodiment, G_(6a) is a chemical bond; in another embodiment,G_(6a) is C₁₋₇ alkylene; in another embodiment, G_(6a) is C₁₋₅ alkylene;in another embodiment, G_(6a) is C₁₋₄ alkylene; in another embodiment,G_(6a) is C₁₋₄ linear alkylene; in another embodiment, G_(6a) is(CH₂)₂—; in another embodiment, G_(6a) is optionally substituted withone or more R**; in another embodiment, G_(6a) is optionally substitutedwith 1, 2, 3 or 4 R**.

In one embodiment, G_(6b) is a chemical bond; in another embodiment,G_(6b) is C₁₋₇ alkylene; in another embodiment, G_(6b) is C₁₋₅ alkylene;in another embodiment, G_(6b) is C₁₋₂ alkylene; in another embodiment,G_(6b) is methylene; in another embodiment, G_(6b) is optionallysubstituted with one or more R**; in another embodiment, G_(6b) isoptionally substituted with 1, 2, 3 or 4 R**; in another embodiment,G_(6b) is optionally substituted with 1 or 2 R**.

In one embodiment, G_(6a) and G_(6b) have a total length of 0 carbonatoms; in another embodiment, G_(6a) and G_(6b) have a total length of 1carbon atom; in another embodiment, G₆a and G_(6b) have a total lengthof 2 carbon atoms; in another embodiment, G_(6a) and G_(6b) have a totallength of 3 carbon atoms; in another embodiment, G_(6a) and G_(6b) havea total length of 4 carbon atoms; in another embodiment, G_(6a) andG_(6b) have a total length of 5 carbon atoms; in another embodiment,G_(6a) and G_(6b) have a total length of 6 carbon atoms; in anotherembodiment, G_(6a) and G_(6b) have a total length of 7 carbon atoms.

In a more specific embodiment, G_(6a) and G_(6b) are independently achemical bond or C₁₋₅ alkylene, which is optionally substituted with 1,2, 3 or 4 R**; G_(6a) and G_(6b) have a total length of 0, 1, 2, 3, 4 or5 carbon atoms.

In another more specific embodiment, G_(6a) is a chemical bond or C₁₋₄alkylene, which is optionally substituted with 1, 2, 3 or 4 R**; G_(6b)is a chemical bond or C₁₋₂ alkylene, which is optionally substitutedwith 1 or 2 R**; G_(6a) and G_(6b) have a total length of 0, 1, 2, 3 or4 carbon atoms.

In another more specific embodiment, G_(6a) is a chemical bond or C₁₋₄alkylene, alternatively C₂₋₄ alkylene, alternatively C₂₋₃ alkylene, morealternatively —(CH₂)₂—; G_(6b) is a chemical bond or methylene; G_(6a)and G_(6b) have a total length of 0, 1, 2, 3 or 4 carbon atoms,alternatively 1, 2, 3 or 4 carbon atoms, alternatively 2 or 3 carbonatoms.

In another more specific embodiment, G_(6a) is a chemical bond or C₁₋₄linear alkylene, alternatively C₂₋₄ linear alkylene, alternatively C₂₋₃linear alkylene, more alternatively —(CH₂)₂—; G_(6b) is a chemical bondor methylene; G_(6a) and G_(6b) have a total length of 0, 1, 2, 3 or 4carbon atoms, alternatively 1, 2, 3 or 4 carbon atoms, alternatively 2or 3 carbon atoms.

R₉

In one embodiment, R₉ is H; in another embodiment, R₉ is C₁₋₈ alkyl; inanother embodiment, R₉ is -L_(c)-OR_(c); in another embodiment, R₉ is-L_(c)-SR_(c); in another embodiment, R₉ is -L_(c)-NR_(c)R′_(c); inanother embodiment, R₉ is C₁₋₆ alkyl.

In a more specific embodiment, R₉ is H, C₁₋₆ alkyl, -L_(c)-OR_(c) or-L_(c)-NR₀R′_(c); in another more specific embodiment, R₉ is H or C₁₋₆alkyl; in another more specific embodiment, R₉ is H.

R₁₀

In one embodiment, R₁₀ is H; in another embodiment, R₁₀ is C₁₋₈ alkyl;in another embodiment, R₁₀ is -L_(c)-OR_(c); in another embodiment, R₁₀is -L_(c)-SR_(c); in another embodiment, R₁₀ is -L_(c)-NR_(c)R′_(c).

In a more specific embodiment, R₁₀ is H, C₁₋₆ alkyl, -L_(c)-OR_(c) or-L_(c)-NR_(c)R′_(c); in another more specific embodiment, R₁₀ is H.

R**

In one embodiment, R** is H; in another embodiment, R** is C₁₋₈ alkyl;in another embodiment, R** is -L_(c)-OR_(c); in another embodiment, R**is -L_(c)-SR_(c); in another embodiment, R** is -L_(c)-NR_(c)R′_(c); inanother embodiment, R** is C₁₋₆ alkyl.

In a more specific embodiment, R** is H, C₁₋₆ alkyl, -L_(c)-OR_(c) or-L_(c)-NR_(c)R′_(c); in another more specific embodiment, R** is H orC₁₋₆ alkyl; in another more specific embodiment, R** is H.

G₁, G₂, G₃ and G₄

In one embodiment, G₁ is a chemical bond; in another embodiment, G₁ isC₁₋₁₃ alkylene; in another embodiment, G₁ is C₂₋₁₃ alkenylene; inanother embodiment, G₁ is C₂₋₁₃ alkynylene; in another embodiment, G₁ isoptionally substituted with one or more R^(s).

In one embodiment, G₂ is a chemical bond; in another embodiment, G₂ isC₂₋₁₃ alkylene; in another embodiment, G₂ is C₂₋₁₃ alkenylene; inanother embodiment, G₂ is C₂₋₁₃ alkynylene; in another embodiment, G₂ isoptionally substituted with one or more R^(s).

In one embodiment, G₁ and G₂ have a total length of 3 carbon atoms; inanother embodiment, G₁ and G₂ have a total length of 4 carbon atoms; inanother embodiment, G₁ and G₂ have a total length of 5 carbon atoms; inanother embodiment, G₁ and G₂ have a total length of 6 carbon atoms; inanother embodiment, G₁ and G₂ have a total length of 7 carbon atoms; inanother embodiment, G₁ and G₂ have a total length of 8 carbon atoms; inanother embodiment, G₁ and G₂ have a total length of 9 carbon atoms; inanother embodiment, G₁ and G₂ have a total length of 10 carbon atoms; inanother embodiment, G₁ and G₂ have a total length of 11 carbon atoms; inanother embodiment, G₁ and G₂ have a total length of 12 carbon atoms; inanother embodiment, G₁ and G₂ have a total length of 13 carbon atoms.

In a more specific embodiment, -G₁-C(R₅R₆)-G₂- is

In one embodiment, G_(1a) is a chemical bond; in another embodiment,G_(1a) is C₁₋₇ alkylene; in another embodiment, G_(1a) is —CH₂—; inanother embodiment, G_(1a) is —(CH₂)₂—; in another embodiment, G_(1a) is—(CH₂)₃—; in another embodiment, G_(1a) is —(CH₂)₄—; in anotherembodiment, G_(1a) is —(CH₂)₅—; in another embodiment, G_(1a) is—(CH₂)₆—; in another embodiment, G_(1a) is optionally substituted with1, 2, 3, 4 or 5 R^(s).

In one embodiment, G_(1b) is a chemical bond; in another embodiment,G_(1b) is C₁₋₇ alkylene; in another embodiment, G_(1b) is C₁₋₃ alkylene;in another embodiment, G_(1b) is —CH₂—; in another embodiment, G_(1b) is—(CH₂)₂—; in another embodiment, G_(1b) is —(CH₂)₃—; in anotherembodiment, G_(1b) is optionally substituted with 1, 2, 3, 4 or 5 R^(s).

In one embodiment, G_(2a) is a chemical bond; in another embodiment,G_(2a) is C₁₋₇ alkylene; in another embodiment, G_(2a) is C₁₋₃ alkylene;in another embodiment, G_(2a) is optionally substituted with 1, 2, 3, 4or 5 R^(s).

In one embodiment, G_(2b) is a chemical bond; in another embodiment,G_(2b) is C₁₋₇ alkylene; in another embodiment, G_(2b) is C₁₋₄ alkylene;in another embodiment, G_(2b) is —CH₂—; in another embodiment, G_(2b) is—(CH₂)₂—; in another embodiment, G_(2b) is —(CH₂)₃—; in anotherembodiment, G_(2b) is optionally substituted with 1, 2, 3, 4 or 5 R^(s).

In a more specific embodiment, G_(1a), G_(1b), G_(2a) and G_(2b) have atotal length of 1, 2, 3, 4, 5, 6 or 7 carbon atoms; in another morespecific embodiment, G_(1a), G_(1b), G_(2a) and G_(2b) have a totallength of 1, 2, 3, 4, 5 or 6 carbon atoms.

In one embodiment, one of L₃ and L₅ is —(CR^(s)R^(s′))₂—, and the otheris a chemical bond; in another embodiment, one of L₃ and L₅ is—(CHR^(s))₂—, and the other is a chemical bond; in another embodiment,one of L₃ and L₅ is —CH═CH—, and the other is a chemical bond; inanother embodiment, one of L₃ and L₅ is —C≡C—, and the other is achemical bond.

In one embodiment, G₃ is a chemical bond; in another embodiment, G₃ isC₁₋₁₃ alkylene; in another embodiment, G₃ is C₂₋₁₃ alkenylene; inanother embodiment, G₃ is C₂₋₁₃ alkynylene; in another embodiment, G₃ isoptionally substituted with one or more R^(s).

In one embodiment, G₄ is a chemical bond; in another embodiment, G₄ isC₂₋₁₃ alkylene; in another embodiment, G₄ is C₂₋₁₃ alkenylene; inanother embodiment, G₄ is C₂₋₁₃ alkynylene; in another embodiment, G₄ isoptionally substituted with one or more R^(s).

In one embodiment, G₃ and G₄ have a total length of 3 carbon atoms; inanother embodiment, G₃ and G₄ have a total length of 4 carbon atoms; inanother embodiment, G₃ and G₄ have a total length of 5 carbon atoms; inanother embodiment, G₃ and G₄ have a total length of 6 carbon atoms; inanother embodiment, G₃ and G₄ have a total length of 7 carbon atoms; inanother embodiment, G₃ and G₄ have a total length of 8 carbon atoms; inanother embodiment, G₃ and G₄ have a total length of 9 carbon atoms; inanother embodiment, G₃ and G₄ have a total length of 10 carbon atoms; inanother embodiment, G₃ and G₄ have a total length of 11 carbon atoms; inanother embodiment, G₃ and G₄ have a total length of 12 carbon atoms; inanother embodiment, G₃ and G₄ have a total length of 13 carbon atoms.

In a more specific embodiment, -G₃-C(R₇R₈)-G₄- is

In one embodiment, G_(3a) is a chemical bond; in another embodiment,G_(3a) is C₁₋₇ alkylene; in another embodiment, G_(3a) is —CH₂—; inanother embodiment, G_(3a) is —(CH₂)₂—; in another embodiment, G_(3a) is—(CH₂)₃—; in another embodiment, G_(3a) is —(CH₂)₄—; in anotherembodiment, G_(3a) is —(CH₂)₅—; in another embodiment, G_(3a) is—(CH₂)₆—; in another embodiment, G_(3a) is optionally substituted with1, 2, 3, 4 or 5 R^(s).

In one embodiment, G_(3b) is a chemical bond; in another embodiment,G_(3b) is C₁₋₇ alkylene; in another embodiment, G_(3b) is C₁₋₃ alkylene;in another embodiment, G_(3b) is —CH₂—; in another embodiment, G_(3b) is—(CH₂)₂—; in another embodiment, G_(3b) is —(CH₂)₃—; in anotherembodiment, G_(3b) is optionally substituted with 1, 2, 3, 4 or 5 R^(s).

In one embodiment, G_(4a) is a chemical bond; in another embodiment,G_(4a) is C₁₋₇ alkylene; in another embodiment, G_(4a) is C₁₋₃ alkylene;in another embodiment, G_(4a) is optionally substituted with 1, 2, 3, 4or 5 R^(s).

In one embodiment, G_(4b) is a chemical bond; in another embodiment,G_(4b) is C₁₋₇ alkylene; in another embodiment, G_(4b) is C₁₋₄ alkylene;in another embodiment, G_(4b) is —CH₂—; in another embodiment, G_(4b) is—(CH₂)₂—; in another embodiment, G_(4b) is —(CH₂)₃—; in anotherembodiment, G_(4b) is optionally substituted with 1, 2, 3, 4 or 5 R^(s);

In a more specific embodiment, G_(3a), G_(3b), G_(4a) and G_(4b) have atotal length of 1, 2, 3, 4, 5, 6 or 7 carbon atoms; in another morespecific embodiment, G_(3a), G_(3b), G_(4a) and G_(4b) have a totallength of 1, 2, 3, 4, 5 or 6 carbon atoms.

In one embodiment, one of L₄ and L₆ is —(CR^(s)R^(s′))₂—, and the otheris a chemical bond; in another embodiment, one of L₄ and L₆ is—(CHR^(s))₂—, and the other is a chemical bond; in another embodiment,one of L₄ and L₆ is —CH═CH—, and the other is a chemical bond; inanother embodiment, one of L₄ and L₆ is —C≡C—, and the other is achemical bond.

In a more specific embodiment, one of L₃ and L₅, or one of L₄ and L₆ is—(CHR^(s))₂—, —CH═CH— or —C≡C—, and the other is a chemical bond;

-   -   G_(1a) and G_(3a) are independently a chemical bond or C₁₋₇        alkylene;    -   G_(1b) and G_(3b) are independently a chemical bond or C₁₋₃        alkylene;    -   G_(2a) and G_(4a) are independently a chemical bond or C₁₋₃        alkylene;    -   G_(2b) and G_(4b) are independently a chemical bond or C₁₋₄        alkylene;    -   G_(1a), G_(1b), G_(2a) and G_(2b) have a total length of 1, 2,        3, 4, 5, 6 or 7 carbon atoms;    -   G_(3a), G_(3b), G_(4a) and G_(4b) have a total length of 1, 2,        3, 4, 5, 6 or 7 carbon atoms.

In another more specific embodiment, one of L₃ and L₅, or one of L₄ andL₆ is —(CH₂)₂—, —CH═CH— or —C≡C—, and the other is a chemical bond;

-   -   G_(1a) and G_(3a) are independently a chemical bond, —CH₂—,        —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—, —(CH₂)₅— or —(CH₂)₆—;    -   G_(1b) and G_(3b) is a chemical bond;    -   G_(2a) and G_(4a) is a chemical bond;    -   G_(2b) and G_(4b) are independently a chemical bond, —CH₂—,        —(CH₂)₂— or —(CH₂)₃—;    -   G_(1a), G_(1b), G_(2a) and G_(2b) have a total length of 1, 2,        3, 4, 5 or 6 carbon atoms;    -   G_(3a), G_(3b), G_(4a) and G_(4b) have a total length of 1, 2,        3, 4, 5 or 6 carbon atoms.

Alternatively, R^(s) and R^(s′) are independently H, C₁₋₁₀ alkyl,-L_(d)-OR_(d) or -L_(d)-NR_(d)R′_(d); alternatively H or C₁₋₆ alkyl;more alternatively H.

In a more specific embodiment, -G_(1a)-L₃-G_(1b)- or -G_(3a)-L₄-G_(3b)-is independently selected from: —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—, —(CH₂)₅—,—(CH₂)₆—, —(CH₂)₇—, —(CH₂)₈—, —(CH₂)₃—CH═CH—, —(CH₂)₃—C≡C—,—(CH₂)₂—CH═CH— and —(CH₂)₂—C≡C—.

In a more specific embodiment, -G_(2a)-L₅-G_(2b)- or -G_(4a)-L₆-G_(4b)-is independently selected from: a chemical bond, —CH₂—, —(CH₂)₂—,—(CH₂)₃—, —CH═CH—CH₂—, —C≡C— and —C═C—CH₂—.

In a more specific embodiment,

have a total length of 4, 5, 6, 7, 8 or 9 carbon atoms.

In a more specific embodiment,

is independently selected from: —(CH₂)₃—C(CH₃)₂—, —(CH₂)₄—C(CH₃)₂—,—(CH₂)₅—C(CH₃)₂—, —(CH₂)₆—C(CH₃)₂—, —(CH₂)₇—C(CH₃)₂—, —(CH₂)₈—C(CH₃)₂—,—(CH₂)₃—CH═CH—C(CH₃)₂—, —(CH₂)₃—C—C—C(CH₃)₂—, —(CH₂)₄—C(CH₃)₂—CH₂—,—(CH₂)₃—C(CH₃)₂—(CH₂)₂—, —(CH₂)₂—C(CH₃)₂—(CH₂)₃—,—(CH₂)₂—CH═CH—C(CH₃)₂—CH₂—, —(CH₂)₂—C(CH₃)₂—C—C—CH₂—,—(CH₂)₂—C(CH₃)₂—CH═CH—CH₂—, —(CH₂)₂—C—C—C(CH₃)₂—CH₂— and—(CH₂)₃—C(CH₃)₂—C═C—; in another more specific embodiment,

is independently —(CH₂)₄—C(CH₃)₂—, —(CH₂)₅—C(CH₃)₂— or —(CH₂)₆—C(CH₃)₂—;in another more specific embodiment,

is —(CH₂)₅—C(CH₃)₂—.

R₃ and R₄

In one embodiment, R₃ is H; in another embodiment, R₃ is C₁₋₁₀ alkyl; inanother embodiment, R₃ is C₁₋₁₀ haloalkyl; in another embodiment, R₃ isC₂₋₁₀ alkenyl; in another embodiment, R₃ is C₂₋₁₀ alkynyl; in anotherembodiment, R₃ is 3- to 14-membered cycloalkyl; in another embodiment,R₃ is 3- to 14-membered heterocyclyl; in another embodiment, R₃ is C₆₋₁₀aryl; in another embodiment, R₃ is 5- to 14-membered heteroaryl; inanother embodiment, R₃ is C₁₋₆ alkyl; in another embodiment, R₃ is C₁₋₆haloalkyl; in another embodiment, R₃ is 3- to 10-membered cycloalkyl; inanother embodiment, R₃ is 3- to 10-membered heterocyclyl; in anotherembodiment, R₃ is 3- to 7-membered cycloalkyl; in another embodiment, R₃is 3- to 7-membered heterocyclyl; in another embodiment, R₃ is Me; inanother embodiment, R₃ is —CH₂CH₃; in another embodiment, R₃ is—CH₂CH₂OH; in another embodiment, R₃ is —CH(CH₃)₂; in anotherembodiment, R₃ is substituted with one or more R*; in anotherembodiment, R₃ is optionally substituted with 1, 2, 3, 4 or 5 R*.

In one embodiment, R₄ is H; in another embodiment, R₄ is C₁₋₁₀ alkyl; inanother embodiment, R₄ is C₁₋₁₀ haloalkyl; in another embodiment, R₄ isC₂₋₁₀ alkenyl; in another embodiment, R₄ is C₂₋₁₀ alkynyl; in anotherembodiment, R₄ is 3- to 14-membered cycloalkyl; in another embodiment,R₄ is 3- to 14-membered heterocyclyl; in another embodiment, R₄ is C₆₋₁₀aryl; in another embodiment, R₄ is 5- to 14-membered heteroaryl; inanother embodiment, R₄ is C₁₋₆ alkyl; in another embodiment, R₄ is C₁₋₆haloalkyl; in another embodiment, R₄ is 3- to 10-membered cycloalkyl; inanother embodiment, R₄ is 3- to 10-membered heterocyclyl; in anotherembodiment, R₄ is 3- to 7-membered cycloalkyl; in another embodiment, R₄is 3- to 7-membered heterocyclyl; in another embodiment, R₄ is Me; inanother embodiment, R₄ is substituted with one or more R*; in anotherembodiment, R₄ is optionally substituted with 1, 2, 3, 4 or 5 R*.

In one embodiment, R₃, R₄ are taken together with the N atom to whichthey are attached to form 3- to 14-membered heterocyclyl; in anotherembodiment, R₃, R₄ are taken together with the N atom to which they areattached to form 3- to 10-membered heterocyclyl; in another embodiment,R₃, R₄ are taken together with the N atom to which they are attached toform 3- to 7-membered heterocyclyl; in another embodiment, R₃, R₄ aretaken together with the N atom to which they are attached to form 5- to7-membered heterocyclyl; in another embodiment, R₃, R₄ are takentogether with the N atom to which they are attached to form 4- to6-membered heterocyclyl; in another embodiment, R₃, R₄ are takentogether with the N atom to which they are attached to form 5-memberedheterocyclyl; in another embodiment, R₃, R₄ are taken together with theN atom to which they are attached to form

in another embodiment, R₃, R₄ are taken together with the N atom towhich they are attached to form

in another embodiment, R₃, R₄ are taken together with the N atom towhich they are attached to form

in another embodiment, R₃, R₄ are taken together with the N atom towhich they are attached to form

in another embodiment, the heterocyclyl formed by R₃ and R₄ takentogether with the N atom to which they are attached is optionallysubstituted with one or more R*; in another embodiment, the heterocyclylformed by R₃ and R₄ taken together with the N atom to which they areattached is optionally substituted with 1, 2, 3, 4 or 5 R*.

In one embodiment, R₄, R₉ are taken together with the atom to which theyare attached to form 3- to 14-membered heterocyclyl or 5- to 14-memberedheteroaryl; in another embodiment, R₄, R₉ are taken together with theatom to which they are attached to form 3- to 10-membered heterocyclyl;in another embodiment, R₄, R₉ are taken together with the atom to whichthey are attached to form 3- to 7-membered heterocyclyl; in anotherembodiment, R₄, R₉ are taken together with the atom to which they areattached to form 6-membered heterocyclyl; in another embodiment, R₄, R₉are taken together with the atom to which they are attached to form

in another embodiment, the heterocyclyl formed by R₄ and R₉ takentogether with the atom to which they are attached is optionallysubstituted with one or more R*; in another embodiment, the heterocyclylformed by R₄ and R₉ taken together with the atom to which they areattached is optionally substituted with 1, 2, 3, 4 or 5 R*.

In a more specific embodiment, R₃ and R₄ are independently H, C₁₋₆alkyl, C₁₋₆ haloalkyl, 3- to 10-membered cycloalkyl or 3- to 10-memberedheterocyclyl, which is optionally substituted with 1, 2, 3, 4 or 5 R*;

-   -   or, R₃ and R₄ are taken together with the N atom to which they        are attached to form 3- to 10-membered heterocyclyl, which is        optionally substituted with 1, 2, 3, 4 or 5 R*;    -   or, R₄ and R₉ are taken together with the atoms to which they        are attached to form 3- to 10-membered heterocyclyl, which is        optionally substituted with 1, 2, 3 or 4 R*.

In another more specific embodiment, R₃ and R₄ are independently H, C₁₋₆alkyl, C₁₋₆ haloalkyl, 3- to 7-membered cycloalkyl or 3- to 7-memberedheterocyclyl, which is optionally substituted with 1, 2, 3, 4 or 5 R*;

-   -   or, R₃ and R₄ are taken together with the N atom to which they        are attached to form 3- to 7-membered heterocyclyl, which is        optionally substituted with 1, 2, 3, 4 or 5 R*;    -   or, R₄ and R₉ are taken together with the atoms to which they        are attached to form 3- to 7-membered heterocyclyl, which is        optionally substituted with 1, 2, 3, 4 or 5 R*.

In a more specific embodiment, R₃ and R₄ are independently C₁₋₆ alkyl,which is optionally substituted with 1, 2, 3, 4 or 5 R*;

-   -   or, R₃ and R₄ are taken together with the N atom to which they        are attached to form 5- to 7-membered heterocyclyl,        alternatively 4- to 6-membered heterocyclyl, more alternatively        5-membered heterocyclyl, which is optionally substituted with 1,        2, 3, 4 or 5 R*;    -   or, R₄ and R₉ are taken together with the atoms to which they        are attached to form 6-membered heterocyclyl, which is        optionally substituted with 1, 2, 3, 4 or 5 R*.

In a more specific embodiment, R₃ is Me, —CH₂CH₃, —CH₂CH₂OH or—CH(CH₃)₂, alternatively Me, —CH₂CH₃ or —CH(CH₃)₂, more alternatively Meor —CH₂CH₃; R₄ is Me;

-   -   or, R₃ and R₄ are taken together with the N atom to which they        are attached to form

-   -    alternatively

-   -    more alternatively

-   -   or, R₄ and R₉ are taken together with the atoms to which they        are attached to form

R*

In one embodiment, R* is H; in another embodiment, R* is halogen; inanother embodiment, R* is cyano; in another embodiment, R* is C₁₋₁₀alkyl; in another embodiment, R* is C₁₋₁₀ haloalkyl; in anotherembodiment, R* is -L_(b)-OR_(b); in another embodiment, R* is-L_(b)-SR_(b); in another embodiment, R* is -L_(b)-NR_(b)R′_(b); inanother embodiment, R* is C₁₋₆ alkyl; in another embodiment, R* is C₁₋₆haloalkyl; in another embodiment, R* is —OR_(b).

In a more specific embodiment, R* is independently H, halogen, cyano,C₁₋₆ alkyl, C₁₋₆ haloalkyl, -L_(b)-OR_(b) or -L_(b)-NR_(b)R′_(b); inanother more specific embodiment, R* is independently H, C₁₋₆ alkyl,C₁₋₆ haloalkyl or —OR_(b); in another more specific embodiment, R* isindependently H, halogen, C₁₋₆ alkyl or C₁₋₆ haloalkyl; in another morespecific embodiment, R* is independently H, C₁₋₆ alkyl or C₁₋₆haloalkyl; in another more specific embodiment, R* is H, Me or OH; inanother more specific embodiment, R* is H or Me.

R₅, R₆, R₇ and R₈

In one embodiment, R₅ is C₁₋₈ alkyl; in another embodiment, R₅ is C₁₋₆alkyl; in another embodiment, R₅ is C₁₋₃ alkyl; in another embodiment,R₅ is Me; in another embodiment, R₅ is optionally substituted with oneor more R*; in another embodiment, R₅ is optionally substituted with 1,2, 3, 4 or 5 R*.

In one embodiment, R₆ is C₁₋₈ alkyl; in another embodiment, R₆ is C₁₋₆alkyl; in another embodiment, R₆ is C₁₋₃ alkyl; in another embodiment,R₆ is Me; in another embodiment, R₆ is optionally substituted with oneor more R*; in another embodiment, R₆ is optionally substituted with 1,2, 3, 4 or 5 R*.

In one embodiment, R₇ is C₁₋₈ alkyl; in another embodiment, R₇ is C₁₋₆alkyl; in another embodiment, R₇ is C₁₋₃ alkyl; in another embodiment,R₇ is Me; in another embodiment, R₇ is optionally substituted with oneor more R*; in another embodiment, R₇ is optionally substituted with 1,2, 3, 4 or 5 R*.

In one embodiment, R₈ is C₁₋₈ alkyl; in another embodiment, R₈ is C₁₋₆alkyl; in another embodiment, R₈ is C₁₋₃ alkyl; in another embodiment,R₈ is Me; in another embodiment, R₈ is optionally substituted with oneor more R*; in another embodiment, R₈ is optionally substituted with 1,2, 3, 4 or 5 R*.

R₁ and R₂

In one embodiment, R₁ is C₄₋₂₀ alkyl; in another embodiment, R₁ is C₄₋₂₀alkenyl; in another embodiment, R₁ is C₄₋₂₀ alkynyl; in anotherembodiment, R₁ is optionally substituted with one or more R; in anotherembodiment, one or more methylene units in R₁ are optionally andindependently replaced by —NR″—.

In a more specific embodiment, R₁ is -G₇-L₁-G₈-H.

In one embodiment, G₇ is a chemical bond; in another embodiment, G₇ isC₁₋₁₂ alkylene; in another embodiment, G₇ is C₁₋₆ alkylene; in anotherembodiment, G₇ is C₁₋₈ alkylene; in another embodiment, G₇ is C₁₋₅linear alkylene; in another embodiment, G₇ is —CH₂—; in anotherembodiment, G₇ is —(CH₂)₂—; in another embodiment, G₇ is —(CH₂)₄—; inanother embodiment, G₇ is —(CH₂)₅—; in another embodiment, G₇ isoptionally substituted with 1, 2, 3, 4, 5 or 6 R; in another embodiment,1, 2 or 3 methylenes in G₇ are optionally and independently substitutedwith 1 R; in another embodiment, 1 or 2 methylenes in G₇ are optionallyand independently substituted with 1 R; in another embodiment, themethylene of G₇ that is collected to M₁ is not substituted with R.

In one embodiment, G₈ is a chemical bond; in another embodiment, G₈ isC₁₋₁₂ alkylene; in another embodiment, G₈ is C₁₋₁₀ alkylene; in anotherembodiment, G₈ is C₁₋₈ alkylene; in another embodiment, G₈ is C₁₋₈linear alkylene; in another embodiment, G₈ is —(CH₂)₂—; in anotherembodiment, G₈ is —(CH₂)₄—; in another embodiment, G₈ is —(CH₂)₆—; inanother embodiment, G₈ is —(CH₂)₇—; in another embodiment, G₈ is—(CH₂)₈—; in another embodiment, G₈ is optionally substituted with 1, 2,3, 4, 5 or 6 R; in another embodiment, 1, 2 or 3 methylenes in G₈ areoptionally and independently substituted with 1 R; in anotherembodiment, 1 or 2 alkylene in G₈ are optionally and independentlysubstituted with 1 R.

In one embodiment, G₇ and G₈ have a total length of 4 carbon atoms; inanother embodiment, G₇ and G₈ have a total length of 5 carbon atoms; inanother embodiment, G₇ and G₈ have a total length of 6 carbon atoms; inanother embodiment, G₇ and G₈ have a total length of 7 carbon atoms; inanother embodiment, G₇ and G₈ have a total length of 8 carbon atoms; inanother embodiment, G₇ and G₈ have a total length of 9 carbon atoms; inanother embodiment, G₇ and G₈ have a total length of 10 carbon atoms; inanother embodiment, G₇ and G₈ have a total length of 11 carbon atoms; inanother embodiment, G₇ and G₈ have a total length of 12 carbon atoms.

In a more specific embodiment, G₇ and G₈ have a total length of 6, 7, 8,9 or 10 carbon atoms.

In a more specific embodiment, G₇ and G₈ have a total length of 6, 7 or8 carbon atoms.

In one embodiment, L₁ is —(CRR′)₂—; in another embodiment, L₁ is—CH═CH—; in another embodiment, L₁ is —C≡C—; in another embodiment, L₁is —NR″—; in another embodiment, L₁ is —(CHR)₂—.

In one embodiment, R₂ is C₄₋₂₀ alkyl; in another embodiment, R₂ is C₄₋₂₀alkenyl; in another embodiment, R₂ is C₄₋₂₀ alkynyl; in anotherembodiment, R₂ is optionally substituted with one or more R; in anotherembodiment, one or more methylene units in R₂ are optionally andindependently replaced by —NR″—.

In a more specific embodiment, R₂ is -G₉-L₂-G₁₀-H.

In one embodiment, G₉ is a chemical bond; in another embodiment, G₉ isC₁₋₁₂ alkylene; in another embodiment, G₉ is C₁₋₆ alkylene; in anotherembodiment, G₉ is C₁₋₅ alkylene; in another embodiment, G₉ is C₁₋₅linear alkylene; in another embodiment, G₉ is —CH₂—; in anotherembodiment, G₉ is —(CH₂)₂—; in another embodiment, G₉ is —(CH₂)₄—; inanother embodiment, G₉ is —(CH₂)₅—; in another embodiment, G₉ isoptionally substituted with 1, 2, 3, 4, 5 or 6 R; in another embodiment,1, 2 or 3 methylenes in G₉ are optionally and independently substitutedwith 1 R; in another embodiment, 1 or 2 methylenes in G₉ are optionallyand independently substituted with 1 R; in another embodiment, themethylene of G₉ that is collected to M₂ is not substituted with R.

In one embodiment, G₁₀ is a chemical bond; in another embodiment, G₁₀ isC₁₋₁₂ alkylene; in another embodiment, G₁₀ is C₁₋₁₀ alkylene; in anotherembodiment, G₁₀ is C₁₋₈ alkylene; in another embodiment, G₁₀ is C₁₋₈linear alkylene; in another embodiment, G₁₀ is —(CH₂)₂—; in anotherembodiment, G₁₀ is —(CH₂)₄—; in another embodiment, G₁₀ is —(CH₂)₆—; inanother embodiment, G₁₀ is —(CH₂)₇—; in another embodiment, G₁₀ is—(CH₂)₈—; in another embodiment, G₁₀ is optionally substituted with 1,2, 3, 4, 5 or 6 R; in another embodiment, 1, 2 or 3 methylenes in G₁₀are optionally and independently substituted with 1 R; in anotherembodiment, 1 or 2 methylenes in G₁₀ are optionally and independentlysubstituted with 1 R.

In one embodiment, G₉ and G₁₀ have a total length of 4 carbon atoms; inanother embodiment, G₉ and G₁₀ have a total length of 5 carbon atoms; inanother embodiment, G₉ and G₁₀ have a total length of 6 carbon atoms; inanother embodiment, G₉ and G₁₀ have a total length of 7 carbon atoms; inanother embodiment, G₉ and G₁₀ have a total length of 8 carbon atoms; inanother embodiment, G₉ and G₁₀ have a total length of 9 carbon atoms; inanother embodiment, G₉ and G₁₀ have a total length of 10 carbon atoms;in another embodiment, G₉ and G₁₀ have a total length of 11 carbonatoms; in another embodiment, G₉ and G₁₀ have a total length of 12carbon atoms.

In a more specific embodiment, G₉ and G₁₀ have a total length of 6, 7,8, 9 or 10 carbon atoms.

In a more specific embodiment, G₉ and G₁₀ have a total length of 6, 7 or8 carbon atoms.

In one embodiment, L₂ is —(CRR′)₂—; in another embodiment, L₂ is—CH═CH—; in another embodiment, L₂ is —C≡C—; in another embodiment, L₂is —NR″—; in another embodiment, L₁ is —(CHR)₂—.

In a more specific embodiment, L₁ and L₂ are independently —(CRR′)₂—,—CH═CH—, —C≡C— or —NR″—;

-   -   G₇, G₈, G₉ and G₁₀ are independently a chemical bond or C₁₋₁₂        alkylene, which is optionally substituted with 1, 2, 3, 4, 5 or        6 R;    -   G₇ and G₈ have a total length of 4, 5, 6, 7, 8, 9, 10, 11 or 12        carbon atoms;    -   G₉ and G₁₀ have a total length of 4, 5, 6, 7, 8, 9, 10, 11 or 12        carbon atoms;    -   1, 2 or 3 methylenes in G₇, G₈, G₉ or G₁₀ are optionally and        independently substituted with 1 R;    -   R′ is independently H, C₁₋₂₀ alkyl, -L_(a)-OR_(a) or        -L_(a)-NR_(a)R′_(a).

In another more specific embodiment, L₁ and L₂ are independently—(CHR)₂—, —CH═CH—, —C≡C— or —NR″—;

-   -   G₇ and G₉ are independently a chemical bond or C₁₋₆ alkylene;    -   G₈ and G₁₀ are independently C₁₋₁₀ alkylene;    -   G₇ and G₈ have a total length of 4, 5, 6, 7, 8, 9 or 10 carbon        atoms;    -   G₉ and G₁₀ have a total length of 4, 5, 6, 7, 8, 9 or 10 carbon        atoms;    -   1, 2 or 3 methylenes in G₇, G₈, G₉ or G₁₀ are optionally and        independently substituted with 1 R.

In another more specific embodiment, L₁ and L₂ are independently—(CHR)₂—, —CH═CH—, —C≡C— or —NR″—;

-   -   G₇ and G₉ are independently a chemical bond or C₁₋₅ alkylene,        alternatively a chemical bond or C₁₋₅ linear alkylene;    -   G₈ and G₁₀ are independently C₁₋₈ alkylene, alternatively C₁₋₈        linear alkylene;    -   G₇ and G₈ have a total length of 4, 5, 6, 7, 8, 9, 10 carbon        atoms, alternatively 6, 7, 8, 9, 10 carbon atoms;    -   G₉ and G₁₀ have a total length of 4, 5, 6, 7, 8, 9, 10 carbon        atoms, alternatively 6, 7, 8, 9, 10 carbon atoms;    -   1 or 2 methylenes in G₇, G₈, G₉ or G₁₀ are optionally and        independently substituted with 1 R.

Alternatively, the methylene collected to M₁ and M₂ is not substitutedwith R.

In another more specific embodiment, L₁ and L₂ are independently—(CHR)₂—, —CH═CH—, —C≡C— or —NR″—;

-   -   G₇ and G₉ are independently a chemical bond, —CH₂—, —(CH₂)₂—,        —(CH₂)₄— or —(CH₂)₅—;    -   G₈ and G₁₀ are independently —(CH₂)₂—, —(CH₂)₄—, —(CH₂)₆—,        —(CH₂)₇— or —(CH₂)₈—;    -   G₇ and G₈ have a total length of 4, 5, 6, 7, 8, 9, 10 carbon        atoms, alternatively 6, 7, 8, 9, 10 carbon atoms;    -   G₉ and G₁₀ have a total length of 4, 5, 6, 7, 8, 9, 10 carbon        atoms, alternatively 6, 7, 8, 9, 10 carbon atoms;    -   1 or 2 methylenes in G₇, G₈, G₉ or G₁₀ are optionally and        independently substituted with 1 R.

Alternatively, the methylene collected to M₁ and M₂ is not substitutedwith R.

In another more specific embodiment, -G₇-L₁-G₈-H or -G₉-L₂-G₁₀-H isindependently selected from: —(CH₂)₅CH₃, —(CH₂)₆CH₃, —(CH₂)₇CH₃,—(CH₂)₈CH₃, —(CH₂)₉CH₃, —(CH₂)₁₀CH₃, —(CH₂)₁₁CH₃, —CH₂—C≡C—(CH₂)₅CH₃,—CH₂—C≡C—(CH₂)₆CH₃, —(CH₂)₂—C≡C—(CH₂)₅CH₃, —(CH₂)₄—C≡C—(CH₂)₃CH₃,—CH₂—CH═CH—(CH₂)₅CH₃, —CH₂—CH═CH—(CH₂)₆CH₃, —(CH₂)₂—CH═CH—(CH₂)₅CH₃,—(CH₂)₄—CH═CH—(CH₂)₃CH₃, —(CH₂)₅—CH═CH—CH₂CH₃,

R^(s)

In one embodiment, R^(s) is H; in another embodiment, R^(s) is C₁₋₁₄alkyl; in another embodiment, R^(s) is -L_(d)-OR_(d); in anotherembodiment, R^(s) is -L_(d)-SR_(d); in another embodiment, R^(s) is-L_(d)-NR_(d)R′_(d); in another embodiment, R^(s) is C₁₋₁₀ alkyl; inanother embodiment, R^(s) is C₁₋₆ alkyl.

In a more specific embodiment, R^(s) is H, C₁₋₁₀ alkyl, -L_(d)-OR_(d) or-L_(d)-NR_(d)R′_(d); in another more specific embodiment, R^(s) is H orC₁₋₆ alkyl.

R

In one embodiment, R is H; in another embodiment, R is C₁₋₂₀ alkyl; inanother embodiment, R is -L_(a)-OR_(a); in another embodiment, R is-L_(a)-SR_(a); in another embodiment, R is -L_(a)-NR_(a)R′_(a); inanother embodiment, R is C₁₋₁₀ alkyl; in another embodiment, R is C₁₋₈alkyl; in another embodiment, R is C₁₋₈ linear alkyl.

In a more specific embodiment, R is H, Me, —(CH₂)₃CH₃, —(CH₂)₄CH₃,—(CH₂)₅CH₃, —(CH₂)₆CH₃ or —(CH₂)₇CH₃.

R″

In one embodiment, R″ is H; in another embodiment, R″ is C₁₋₂₀ alkyl; inanother embodiment, R″ is C₁₋₁₄ alkyl; in another embodiment, R″ isC₁₋₁₀ alkyl; in another embodiment, R″ is C₇₋₉ alkyl; in anotherembodiment, R″ is —(CH₂)₇CH₃.

L_(a) and L_(e)

In one embodiment, L_(a) and L_(e) are independently a chemical bond; inanother embodiment, L_(a) and L_(e) are independently C₁₋₂₀ alkylene; inanother embodiment, L_(a) and L_(e) are independently C₁₋₁₄ alkylene; inanother embodiment, L_(a) and L_(e) are independently C₁₋₁₀ alkylene.

L_(b) and L_(f)

In one embodiment, L_(b) and L_(f) are independently a chemical bond; inanother embodiment, L_(b) and L_(f) are independently C₁₋₁₀ alkylene; inanother embodiment, L_(b) and L_(f) are independently C₁₋₆ alkylene.

L_(c)

In one embodiment, L_(e) is a chemical bond; in another embodiment,L_(c) is C₁₋₈ alkylene; in another embodiment, L_(c) is C₁₋₆ alkylene.

L_(d)

In one embodiment, L_(d) is a chemical bond; in another embodiment,L_(d) is C₁₋₁₄ alkylene; in another embodiment, L_(d) is C₁₋₁₀ alkylene.

R_(a) and R′_(a)

In one embodiment, R_(a) is H; in another embodiment, R_(a) is C₁₋₂₀alkyl; in another embodiment, R_(a) is 3- to 14-membered cycloalkyl; inanother embodiment, R_(a) is 3- to 14-membered heterocyclyl; in anotherembodiment, R_(a) is C₁₋₁₄ alkyl; in another embodiment, R_(a) is C₁₋₁₀alkyl; in another embodiment, R_(a) is C₈₋₁₀ alkyl; in anotherembodiment, R_(a) is C₈₋₁₀ linear alkyl; in another embodiment, R_(a) is—(CH₂)₈CH₃; in another embodiment, R_(a) is optionally substituted withone or more of the following substituents: H, C₁₋₂₀ alkyl,-L_(e)-OR_(e), -L_(e)-SR_(e) and -L_(e)-NR_(e)R′_(e).

In one embodiment, R′_(a) is H; in another embodiment, R′_(a) is C₁₋₂₀alkyl; in another embodiment, R′_(a) is 3- to 14-membered cycloalkyl; inanother embodiment, R′_(a) is 3- to 14-membered heterocyclyl; in anotherembodiment, R′_(a) is C₁₋₁₄ alkyl; in another embodiment, R′_(a) isC₁₋₁₀ alkyl; in another embodiment, R′_(a) is C₈₋₁₀ alkyl; in anotherembodiment, R′_(a) is C₈₋₁₀ linear alkyl; in another embodiment, R′_(a)is —(CH₂)₈CH₃; in another embodiment, R′_(a) is optionally substitutedwith one or more of the following substituents: H, C₁₋₂₀ alkyl,-L_(e)-OR_(e), -L_(e)-SR_(e) and -L_(e)-NR_(e)R′_(e).

R_(b) and R′_(b)

In one embodiment, R_(b) is H; in another embodiment, R_(b) is C₁₋₁₀alkyl; in another embodiment, R_(b) is 3- to 14-membered cycloalkyl; inanother embodiment, R_(b) is 3- to 14-membered heterocyclyl; in anotherembodiment, R_(b) is C₁₋₆ alkyl; in another embodiment, R_(b) is 3- to10-membered cycloalkyl; in another embodiment, R_(b) is 3- to10-membered heterocyclyl; in another embodiment, R_(b) is optionallysubstituted with one or more of the following substituents: H, C₁₋₁₀alkyl, -L_(f)-OR_(f), -L_(f)-SR_(f) and -L_(f)-NR_(f)R′_(f).

In one embodiment, R′_(b) is H; in another embodiment, R′_(b) is C₁₋₁₀alkyl; in another embodiment, R′_(b) is 3- to 14-membered cycloalkyl; inanother embodiment, R′_(b) is 3- to 14-membered heterocyclyl; in anotherembodiment, R′_(b) is C₁₋₆ alkyl; in another embodiment, R′_(b) is 3- to10-membered cycloalkyl; in another embodiment, R′_(b) is 3- to10-membered heterocyclyl; in another embodiment, R_(b) is optionallysubstituted with one or more of the following substituents: H, C₁₋₁₀alkyl, -L_(f)-OR_(f), -L_(f)-SR_(f) and -L_(f)-NR_(f)R′_(f).

R_(c) and R′_(c)

In one embodiment, R_(c) is H; in another embodiment, R_(c) is C₁₋₈alkyl; in another embodiment, R_(c) is C₁₋₆ alkyl.

In one embodiment, R′_(c) is H; in another embodiment, R′_(c) is C₁₋₈alkyl; in another embodiment, R′_(c) is C₁₋₆ alkyl.

R_(d) and R′_(a)

In one embodiment, R_(d) is H; in another embodiment, R_(d) is C₁₋₁₄alkyl; in another embodiment, R_(d) is C₁₋₁₀ alkyl. In one embodiment,R′d is H; in another embodiment, R′d is C₁₋₁₄ alkyl; in anotherembodiment, R′d is C₁₋₁₀ alkyl.

R_(e) and R′_(e)

In one embodiment, R_(e) is H; in another embodiment, R_(e) is C₁₋₂₀alkyl.

In one embodiment, R′_(e) is H; in another embodiment, R′_(e) is C₁₋₂₀alkyl.

R_(f) and R′_(f)

In one embodiment, R_(f) is H; in another embodiment, R_(f) is C₁₋₁₀alkyl.

In one embodiment, R′_(f) is H; in another embodiment, R′_(f) is C₁₋₁₀alkyl.

Any of the above technical solutions in any specific embodiment or anycombination thereof may be combined with any technical solution or anycombination thereof in other specific embodiments. For example, anytechnical solution of Q, or any combination thereof, may be combinedwith any technical solution of M₁, M₂, G₅, G_(6a), G_(6b), R₉, R₁₀, R**,G₁, G₂, G₃, G₄, R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R, R″, R^(s), Ar₂,L_(a), L_(e), L_(b), L_(f), L_(c), L_(d), R_(a), R′_(a), R_(b), R′_(b),R_(e), R′_(e), R_(d), R′d, R_(e), R′_(e), R_(f) and R′_(f), or anycombination thereof. The present disclosure is intended to include allof these combinations of technical solutions and, for reasons of space,will not be listed.

In a more specific embodiment, the present disclosure provides acompound of formula (IV), or a pharmaceutically acceptable salt,isotopic variant, tautomer or stereoisomer thereof:

-   -   wherein,    -   M₁ and M₂ are independently selected from —C(O)O—, —O—,        —SC(O)O—, —OC(O)NR_(a)—, —NR_(a)C(O)NR_(a)—, —OC(O)S—, —OC(O)O—,        —NR_(a)C(O)O—, —OC(O)—, —SC(O)—, —C(O)S—, —NR_(a)—,        —C(O)NR_(a)—, —NR_(a)C(O)—, —NR_(a)C(O)S—, —SC(O)NR_(a)—,        —C(O)—, —OC(S)—, —C(S)O—, —OC(S)NR_(a)—, —NR_(a)C(S)O—, —S—S—        and —S(O)₀₋₂—;    -   Q is selected from a chemical bond, —C(O)O—, —O—, —SC(O)O—,        —OC(O)NR_(b)—, —NR_(b)C(O)NR_(b)—, —OC(O)S—, —OC(O)O—,        —NR_(b)C(O)O—, —OC(O)—, —SC(O)—, —C(O)S—, —NR_(b)—,        —C(O)NR_(b)—, —NR_(b)C(O)—, —NR_(b)C(O)S—, —SC(O)NR_(b)—,        —C(O)—, —OC(S)—, —C(S)O—, —OC(S)NR_(b)—, —NR_(b)C(S)O—, —S—S—,        —S(O)₀₋₂—, phenylene and pyridylidene, wherein, the phenylene or        pyridylidene is optionally substituted with one or more R*;    -   G₅ is a chemical bond or C₁₋₈ alkylene, which is optionally        substituted with one or more R**;    -   G_(6a) and G_(6b) are independently a chemical bond or C₁₋₇        alkylene, which is optionally substituted with one or more R**;    -   G_(6a) and G_(6b) have a total length of 0, 1, 2, 3, 4, 5, 6 or        7 carbon atoms;    -   R₉, R₁₀ and R** are independently H, C₁₋₈ alkyl, -L_(c)-OR_(c),        -L_(c)-SR_(c) or -L_(c)-NR_(c)R′_(c);    -   G₁, G₂, G₃ and G₄ are independently a chemical bond, C₁₋₁₃        alkylene, C₂₋₁₃ alkenylene or C₂₋₁₃ alkynylene, which is        optionally substituted with one or more R^(s);    -   G₁ and G₂ have a total length of 3, 4, 5, 6, 7, 8, 9, 10, 11, 12        or 13 carbon atoms;    -   G₃ and G₄ have a total length of 3, 4, 5, 6, 7, 8, 9, 10, 11, 12        or 13 carbon atoms;    -   R₃ and R₄ are independently H, C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl,        C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, 3- to 14-membered cycloalkyl, 3-        to 14-membered heterocyclyl, C₆₋₁₀ aryl or 5- to 14-membered        heteroaryl, which is optionally substituted with one or more R*;    -   or, R₃ and R₄ are taken together with the N atom to which they        are attached to form 3- to 14-membered heterocyclyl, which is        optionally substituted with one or more R*;    -   or, R₄ and R₉ are taken together with the atoms to which they        are attached to form 3- to 14-membered heterocyclyl or 5- to        14-membered heteroaryl, which is optionally substituted with one        or more R*;    -   R* is independently H, halogen, cyano, C₁₋₁₀ alkyl, C₁₋₁₀        haloalkyl, -L_(b)-OR_(b), -L_(b)-SR_(b) or -L_(b)-NR_(b)R′_(b);    -   R₅, R₆, R₇ and R₈ are independently C₁₋₈ alkyl, which is        optionally substituted with one or more R*;    -   R₁ and R₂ are independently C₄₋₂₀ alkyl, C₄₋₂₀ alkenyl or C₄₋₂₀        alkynyl, which is optionally substituted with one or more R, and        wherein one or more methylene units are optionally and        independently replaced with —NR″—;    -   R^(s) is independently H, C₁₋₁₄ alkyl, -L_(d)-OR_(d),        -L_(d)-SR_(d) or -L_(d)-NR_(d)R′_(d);    -   R is independently H, C₁₋₂₀ alkyl, -L_(a)-OR_(a), -L_(a)-SR_(a)        or -L_(a)-NR_(a)R′_(a);    -   R″ is independently H or C₁₋₂₀ alkyl;    -   L_(a) and L_(e) are independently a chemical bond or C₁₋₂₀        alkylene;    -   L_(b) and L_(f) are independently a chemical bond or C₁₋₁₀        alkylene;    -   L_(c) is independently a chemical bond or C₁₋₈ alkylene;    -   L_(d) is independently a chemical bond or C₁₋₁₄ alkylene;    -   R_(a) and R′_(a) are independently selected from H, C₁₋₂₀ alkyl,        3- to 14-membered cycloalkyl, and 3- to 14-membered        heterocyclyl, which are optionally substituted with one or more        of the following substituents: H, C₁₋₂₀ alkyl, -L_(c)-OR_(c),        -L_(c)-SR_(c) and -L_(c)-NR_(c)R′_(e);    -   R_(b) and R′_(b) are independently selected from H, C₁₋₁₀ alkyl,        3- to 14-membered cycloalkyl, and 3- to 14-membered        heterocyclyl, which are optionally substituted with one or more        of the following substituents: H, C₁₋₁₀ alkyl, -L_(f)-OR_(f),        -L_(f)-SR_(f) and -L_(f)-NR_(f)R′_(f);    -   R_(c) and R′_(e) are independently H or C₁₋₈ alkyl;    -   R_(d) and R′_(a) are independently H or C₁₋₁₄ alkyl;    -   R_(e) and R′_(e) are independently H or C₁₋₂₀ alkyl;    -   R_(f) and R′_(f) are independently H or C₁₋₁₀ alkyl.

In a more specific embodiment, the present disclosure provides acompound of formula (IV) described above, or a pharmaceuticallyacceptable salt, isotopic variant, tautomer or stereoisomer thereof,wherein, M₁ and M₂ are independently selected from —C(O)O—, —SC(O)O—,—OC(O)NR_(a)—, —NR_(a)C(O)NR_(a)—, —OC(O)S—, —OC(O)O—, —NR_(a)C(O)O—,—C(O)S—, —C(O)NR_(a)—, —NR_(a)C(O)S—, —SC(O)NR_(a)—, —C(S)O—,—OC(S)NR_(a)— and —NR_(a)C(S)O—; alternatively —C(O)O—, —C(O)S—,—C(O)NR_(a)—, and —C(S)O—; alternatively —C(O)O—, —C(O)S— and—C(O)NR_(a)—.

In a more specific embodiment, the present disclosure provides acompound of formula (IV) described above, or a pharmaceuticallyacceptable salt, isotopic variant, tautomer or stereoisomer thereof,wherein, Q is selected from a chemical bond, —C(O)O—, —O—, —SC(O)O—,—OC(O)NR_(b)—, —NR_(b)C(O)NR_(b)—, —OC(O)S—, —OC(O)O—, —NR_(b)C(O)O—,—OC(O)—, —SC(O)—, —C(O)S—, —NR_(b)—, —C(O)NR_(b)—, —NR_(b)C(O)—,—NR_(b)C(O)S—, —SC(O)NR_(b)—, —C(O)—, —OC(S)—, —C(S)O—, —OC(S)NR_(b)—,—NR_(b)C(S)O—, —S—S—, and —S(O)₀₋₂—; alternatively —C(O)O—, —O—,—SC(O)O—, —OC(O)NH—, —NHC(O)NH—, —OC(O)S—, —OC(O)O—, —NHC(O)O—, —OC(O)—,—SC(O)—, —C(O)S—, —NH—, —C(O)NH—, —NHC(O)—, —NHC(O)S—, —SC(O)NH—,—C(O)—, —OC(S)—, —C(S)O—, —OC(S)NH— and —NHC(S)O—; alternatively—C(O)O—, —O—, —SC(O)O—, —OC(O)NH—, —NHC(O)NH—, —OC(O)S—, —OC(O)O— and—NHC(O)O—; more alternatively —C(O)O—.

In a more specific embodiment, the present disclosure provides acompound of formula (IV) described above, or a pharmaceuticallyacceptable salt, isotopic variant, tautomer or stereoisomer thereof,wherein, G₅ is a chemical bond.

In a more specific embodiment, the present disclosure provides acompound of formula (IV) described above, or a pharmaceuticallyacceptable salt, isotopic variant, tautomer or stereoisomer thereof,wherein,

-   -   G_(6a) and G_(6b) are independently a chemical bond or C₁₋₅        alkylene, which is optionally substituted with 1, 2, 3 or 4 R**;    -   G_(6a) and G_(6b) have a total length of 0, 1, 2, 3, 4 or 5        carbon atoms.

Alternatively, G_(6a) is a chemical bond or C₁₋₄ alkylene, which isoptionally substituted with 1, 2, 3 or 4 R**;

-   -   G_(6b) is a chemical bond or C₁₋₂ alkylene, which is optionally        substituted with 1 or 2 R**;    -   G_(6a) and G_(6b) have a total length of 0, 1, 2, 3 or 4 carbon        atoms.

Alternatively, G_(6a) is a chemical bond or C₁₋₄ alkylene, alternativelyC₂₋₄ alkylene, alternatively C₂₋₃ alkylene, more alternatively —(CH₂)₂—;

-   -   G_(6b) is a chemical bond or methylene;    -   G_(6a) and G_(6b) have a total length of 0, 1, 2, 3 or 4 carbon        atoms, alternatively 1, 2, 3 or 4 carbon atoms, alternatively 2        or 3 carbon atoms.

Alternatively, G_(6a) is a chemical bond or C₁₋₄ linear alkylene,alternatively C₂₋₄ linear alkylene, alternatively C₂₋₃ linear alkylene,more alternatively —(CH₂)₂—;

-   -   G_(6b) is a chemical bond or methylene;    -   G_(6a) and G_(6b) have a total length of 0, 1, 2, 3 or 4 carbon        atoms, alternatively 1, 2, 3 or 4 carbon atoms, alternatively 2        or 3 carbon atoms.

In a more specific embodiment, the present disclosure provides acompound of formula (IV) described above, or a pharmaceuticallyacceptable salt, isotopic variant, tautomer or stereoisomer thereof,wherein, R₉ and R** are independently H, C₁₋₆ alkyl, -L_(c)-OR_(c) or-L_(c)-NR_(c)R′_(e), R₁₀ is H.

Alternatively, R₉ and R** are independently H or C₁₋₆ alkyl, R₁₀ is H.

Alternatively, R₉, R** and R₁₀ are H.

In a more specific embodiment, the present disclosure provides acompound of formula (IV) described above, or a pharmaceuticallyacceptable salt, isotopic variant, tautomer or stereoisomer thereof,wherein

-   -   G₁-C(R₅R₆)-G₂- is

-   -    G₃-C(R₇R₈)-G₄- is

-   -   wherein, one of L₃ and L₅, or one of L₄ and L₆ is        —(CR^(s)R^(s′))₂—, —CH═CH— or —C≡C—, and the other is a chemical        bond;    -   G_(1a), G_(1b), G₂a, G₂b, G_(3a), G_(3b), G_(4a) and G_(4b) are        independently a chemical bond or C₁₋₇ alkylene, which is        optionally substituted with 1, 2, 3, 4 or 5 R^(s);    -   G_(1a), G_(1b), G_(2a) and G_(2b) have a total length of 1, 2,        3, 4, 5, 6 or 7 carbon atoms;    -   G_(3a), G_(3b), G_(4a) and G_(4b) have a total length of 1, 2,        3, 4, 5, 6 or 7 carbon atoms;    -   R^(s′) is independently H, C₁₋₁₄ alkyl, -L_(d)-OR_(d) or        -L_(d)-NR_(d)R′_(d);    -   alternatively, one of L₃ and L₅, or one of L₄ and L₆ is        —(CHR^(s))₂—, —CH═CH— or —C≡C—, and the other is a chemical        bond;    -   G_(1a) and G_(3a) are independently a chemical bond or C₁₋₇        alkylene;    -   G_(1b) and G_(3b) are independently a chemical bond or C₁₋₃        alkylene;    -   G_(2a) and G_(4a) are independently a chemical bond or C₁₋₃        alkylene;    -   G_(2b) and G_(4b) are independently a chemical bond or C₁₋₄        alkylene;    -   G_(1a), G_(1b), G_(2a) and G_(2b) have a total length of 1, 2,        3, 4, 5, 6 or 7 carbon atoms;    -   G_(3a), G_(3b), G_(4a) and G₄O have a total length of 1, 2, 3,        4, 5, 6 or 7 carbon atoms.

Alternatively, one of L₃ and L₅, or one of L₄ and L₆ is —(CH₂)₂—,—CH═CH— or —C≡C—, and the other is a chemical bond;

-   -   G_(1a) and G_(3a) are independently a chemical bond, —CH₂—,        —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—, —(CH₂)₅— or —(CH₂)₆—;    -   G_(1b) and G_(3b) is a chemical bond;    -   G_(2a) and G_(4a) is a chemical bond;    -   G_(2b) and G_(4b) are independently a chemical bond, —CH₂—,        —(CH₂)₂— or —(CH₂)₃—;    -   G_(1a), G_(1b), G_(2a) and G_(2b) have a total length of 1, 2,        3, 4, 5 or 6 carbon atoms;    -   G_(3a), G_(3b), G_(4a) and G_(4b) have a total length of 1, 2,        3, 4, 5 or 6 carbon atoms.

Alternatively, R^(s) and R^(s′) are independently H, C₁₋₁₀ alkyl,-L_(d)-OR_(d) or -L_(d)-NR_(d)R′_(d);

-   -   alternatively H or C₁₋₆ alkyl; more alternatively H;    -   alternatively, -G_(1a)-L₃-G_(1b)- or -G_(3a)-L₄-G_(3b)- is        independently selected from the following groups:    -   —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—, —(CH₂)₅—, —(CH₂)₆—, —(CH₂)₇—,        —(CH₂)₈—, —(CH₂)₃—CH═CH—, —(CH₂)₃—C≡C—, —(CH₂)₂—CH═CH— and        —(CH₂)₂—C≡C—;    -   G_(2a)-L₅-G_(2b)- or -G_(4a)-L₆-G_(4b)- is independently        selected from the following groups:    -   a chemical bond, —CH₂—, —(CH₂)₂—, —(CH₂)₃—, —CH═CH—CH₂—, —C≡C—        and —C—C—CH₂—;

-   -    have a total length of 4, 5, 6, 7, 8 or 9 carbon atoms.

Alternatively,

is independently selected from the following groups:

-   -   —(CH₂)₃—C(CH₃)₂—, —(CH₂)₄—C(CH₃)₂—, —(CH₂)₅—C(CH₃)₂—,        —(CH₂)₆—C(CH₃)₂—, —(CH₂)₇—C(CH₃)₂—, —(CH₂)₈—C(CH₃)₂—,        —(CH₂)₃—CH═CH—C(CH₃)₂—, —(CH₂)₃—C—C—C(CH₃)₂—,        —(CH₂)₄—C(CH₃)₂—CH₂—, —(CH₂)₃—C(CH₃)₂—(CH₂)₂—,        —(CH₂)₂—C(CH₃)₂—(CH₂)₃—, —(CH₂)₂—CH═CH—C(CH₃)₂—CH₂—,        —(CH₂)₂—C(CH₃)₂—C—C—CH₂—, —(CH₂)₂—C(CH₃)₂—CH═CH—CH₂—,        —(CH₂)₂—C—C—C(CH₃)₂—CH₂— and —(CH₂)₃—C(CH₃)₂—C≡C—, alternatively        —(CH₂)₄—C(CH₃)₂—, —(CH₂)₅—C(CH₃)₂— and —(CH₂)₆—C(CH₃)₂—, more        alternatively —(CH₂)₅—C(CH₃)₂—.

In a more specific embodiment, the present disclosure provides acompound of formula (IV) described above, or a pharmaceuticallyacceptable salt, isotopic variant, tautomer or stereoisomer thereof,wherein,

-   -   R₃ and R₄ are independently H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, 3- to        10-membered cycloalkyl or 3- to 10-membered heterocyclyl, which        is optionally substituted with 1, 2, 3, 4 or 5 R*;    -   or, R₃ and R₄ are taken together with the N atom to which they        are attached to form 3- to 10-membered heterocyclyl, which is        optionally substituted with 1, 2, 3, 4 or 5 R*;    -   or, R₄ and R₉ are taken together with the atoms to which they        are attached to form 3- to 10-membered heterocyclyl, which is        optionally substituted with 1, 2, 3 or 4 R*.

Alternatively, R₃ and R₄ are independently H, C₁₋₆ alkyl, C₁₋₆haloalkyl, 3- to 7-membered cycloalkyl or 3- to 7-membered heterocyclyl,which is optionally substituted with 1, 2, 3, 4 or 5 R*;

-   -   or, R₃ and R₄ are taken together with the N atom to which they        are attached to form 3- to 7-membered heterocyclyl, which is        optionally substituted with 1, 2, 3, 4 or 5 R*;    -   or, R₄ and R₉ are taken together with the atoms to which they        are attached to form 3- to 7-membered heterocyclyl, which is        optionally substituted with 1, 2, 3, 4 or 5 R*.

Alternatively, R₃ and R₄ are independently C₁₋₆ alkyl, alternativelyC₁₋₃ alkyl, which is optionally substituted with 1, 2, 3, 4 or 5 R*;

-   -   or, R₃ and R₄ are taken together with the N atom to which they        are attached to form 5- to 7-membered heterocyclyl,        alternatively 4- to 6-membered heterocyclyl, more alternatively        5-membered heterocyclyl, which is optionally substituted with 1,        2, 3, 4 or 5 R*;    -   or, R₄ and R₉ are taken together with the atoms to which they        are attached to form 6-membered heterocyclyl, which is        optionally substituted with 1, 2, 3, 4 or 5 R*.

Alternatively, R* is independently H, halogen, cyano, C₁₋₆ alkyl, C₁₋₆haloalkyl, -L_(b)-OR_(b) or -L_(b)-NR_(b)R′_(b); alternatively H, C₁₋₆alkyl, C₁₋₆ haloalkyl or —OR_(b); alternatively H, halogen, C₁₋₆ alkylor C₁₋₆ haloalkyl; alternatively H, C₁₋₆ alkyl or C₁₋₆ haloalkyl;alternatively independently H, Me or OH; more alternatively H or Me.

Alternatively, R₃ is Me, —CH₂CH₃, —CH₂CH₂OH or —CH(CH₃)₂, alternativelyMe, —CH₂CH₃ or —CH(CH₃)₂, more alternatively Me or —CH₂CH₃;

-   -   R₄ is Me;    -   or, R₃ and R₄ are taken together with the N atom to which they        are attached to form

-   -    alternatively

-   -    more alternatively

-   -   or, R₄ and R₉ are taken together with the atoms to which they        are attached to form

In a more specific embodiment, the present disclosure provides acompound of formula (IV) described above, or a pharmaceuticallyacceptable salt, isotopic variant, tautomer or stereoisomer thereof,wherein, R₅, R₆, R₇ and R₈ are independently C₁₋₆ alkyl; alternativelyC₁₋₃ alkyl; more alternatively Me.

Alternatively, R₅, R₆, R₇ and R₈ is optionally substituted with 1, 2, 3,4 or 5 R*.

In a more specific embodiment, the present disclosure provides acompound of formula (IV) described above, or a pharmaceuticallyacceptable salt, isotopic variant, tautomer or stereoisomer thereof,wherein,

-   -   R₁ is -G₇-L₁-G₈-H, R₂ is -G₉-L₂-G₁₀-H, wherein,    -   L₁ and L₂ are independently —(CRR′)₂—, —CH═CH—, —C≡C— or —NR″—;    -   G₇, G₈, G₉ and G₁₀ are independently a chemical bond or C₁₋₁₂        alkylene, which is optionally substituted with 1, 2, 3, 4, 5 or        6 R;    -   G₇ and G₈ have a total length of 4, 5, 6, 7, 8, 9, 10, 11 or 12        carbon atoms;    -   G₉ and G₁₀ have a total length of 4, 5, 6, 7, 8, 9, 10, 11 or 12        carbon atoms;    -   1, 2 or 3 methylenes in G₇, G₈, G₉ or G₁₀ are optionally and        independently substituted with 1 R;    -   R′ is independently H, C₁₋₂₀ alkyl, -L_(a)-OR_(a) or        -L_(a)-NR_(a)R′_(a).

Alternatively, L₁ and L₂ are independently —(CHR)₂—, —CH═CH—, —C≡C— or—NR″—;

-   -   G₇ and G₉ are independently a chemical bond or C₁₋₆ alkylene;    -   G₈ and G₁₀ are independently C₁₋₁₀ alkylene;    -   G₇ and G₈ have a total length of 4, 5, 6, 7, 8, 9 or 10 carbon        atoms;    -   G₉ and G₁₀ have a total length of 4, 5, 6, 7, 8, 9 or 10 carbon        atoms;    -   1, 2 or 3 methylenes in G₇, G₈, G₉ or G₁₀ are optionally and        independently substituted with 1 R.

Alternatively, L₁ and L₂ are independently —(CHR)₂—, —CH═CH—, —C≡C— or—NR″—;

-   -   G₇ and G₉ are independently a chemical bond or C₁₋₅ alkylene,        alternatively a chemical bond or C₁₋₅ linear alkylene;    -   G₈ and G₁₀ are independently C₁₋₈ alkylene, alternatively C₁₋₈        linear alkylene;    -   G₇ and G₈ have a total length of 4, 5, 6, 7, 8, 9, 10 carbon        atoms, alternatively 6, 7, 8, 9, 10 carbon atoms;    -   G₉ and G₁₀ have a total length of 4, 5, 6, 7, 8, 9, 10 carbon        atoms, alternatively 6, 7, 8, 9, 10 carbon atoms;    -   1 or 2 methylenes in G₇, G₈, G₉ or G₁₀ are optionally and        independently substituted with 1 R.

Alternatively, L₁ and L₂ are independently —(CHR)₂—, —CH═CH—, —C≡C— or—NR″—;

-   -   G₇ and G₉ are independently a chemical bond, —CH₂—, —(CH₂)₂—,        —(CH₂)₄— or —(CH₂)₅—;    -   G₈ and G₁₀ are independently —(CH₂)₂—, —(CH₂)₄—, —(CH₂)₆—,        —(CH₂)₇— or —(CH₂)₈—;    -   G₇ and G₈ have a total length of 4, 5, 6, 7, 8, 9, 10 carbon        atoms, alternatively 6, 7, 8, 9, 10 carbon atoms;    -   G₉ and G₁₀ have a total length of 4, 5, 6, 7, 8, 9, 10 carbon        atoms, alternatively 6, 7, 8, 9, 10 carbon atoms;    -   1 or 2 methylenes in G₇, G₈, G₉ or G₁₀ are optionally and        independently substituted with 1 R.

Alternatively, R and R′ are independently H, C₁₋₁₄ alkyl, -L_(a)-OR_(a)or -L_(a)-NR_(a)R′_(a); alternatively H or C₁₋₁₀ alkyl; alternatively Hor C₁₋₈ alkyl; alternatively H or C₁₋₇ alkyl; alternatively H or C₁₋₆alkyl; alternatively H or C₁₋₈ linear alkyl; alternatively H or C₁₋₇linear alkyl; alternatively H or C₁₋₆ linear alkyl; alternatively H, Me,—(CH₂)₃CH₃, —(CH₂)₄CH₃, —(CH₂)₅CH₃, —(CH₂)₆CH₃ or —(CH₂)₇CH₃;alternatively H, Me, —(CH₂)₃CH₃, —(CH₂)₄CH₃, —(CH₂)₅CH₃ or —(CH₂)₆CH₃;more alternatively H, Me, —(CH₂)₃CH₃, —(CH₂)₄CH₃ or —(CH₂)₅CH₃.

Alternatively, R″ is H or C₁₋₁₄ alkyl; alternatively H or C₁₋₁₀ alkyl;alternatively H or C₇₋₉ alkyl; alternatively H or C₇₋₉ linear alkyl;more alternatively —(CH₂)₇CH₃.

Alternatively, -G₇-L₁-G₈-H or -G₉-L₂-G₁₀-H is independently selectedfrom the following groups:

-   -   —(CH₂)₅CH₃, —(CH₂)₆CH₃, —(CH₂)₇CH₃, —(CH₂)₈CH₃, —(CH₂)₉CH₃,        —(CH₂)₁₀CH₃, —(CH₂)₁₁CH₃, —CH₂—C≡C—(CH₂)₅CH₃,        —CH₂—C≡C—(CH₂)₆CH₃, —(CH₂)₂—C≡C—(CH₂)₅CH₃,        —(CH₂)₄—C≡C—(CH₂)₃CH₃, —CH₂—CH═CH—(CH₂)₅CH₃,        —CH₂—CH═CH—(CH₂)₆CH₃, —(CH₂)₂—CH═CH—(CH₂)₅CH₃,        —(CH₂)₄—CH═CH—(CH₂)₃CH₃, —(CH₂)₅—CH═CH—CH₂CH₃,

In a more specific embodiment, the present disclosure provides acompound of formula (IV) described above, or a pharmaceuticallyacceptable salt, isotopic variant, tautomer or stereoisomer thereof,which has the following structural formula:

-   -   wherein,    -   a, a′, b and g are independently 0, 1, 2, 3, 4 or 5, a′ and b        are not 0 at the same time;    -   a′+g=0, 1, 2, 3, 4 or 5;    -   c and e are independently 3, 4, 5, 6, 7, 8 or 9;    -   d and fare independently 0, 1, 2, 3 or 4;    -   c+d=3, 4, 5, 6, 7, 8 or 9, e+f=3, 4, 5, 6, 7, 8 or 9;    -   methylenes in

-   -    or are optionally and independently substituted with 1, 2, 3, 4        or 5 C₁₋₆ alkyl.

The remaining groups are defined in any one of the above.

In a more specific embodiment, the present disclosure provides acompound of formula (V) described above, or a pharmaceuticallyacceptable salt, isotopic variant, tautomer or stereoisomer thereof,wherein,

-   -   Q is selected from —C(O)O—, —O—, —SC(O)O—, —OC(O)NR_(b)—,        —NR_(b)C(O)NR_(b)—, —OC(O)S—, —OC(O)O—, —NR_(b)C(O)O—, —OC(O)—,        —SC(O)—, —C(O)S—, —NR_(b)—, —C(O)NR_(b)—, —NR_(b)C(O)—,        —NR_(b)C(O)S—, —SC(O)NR_(b)—, —C(O)—, —OC(S)—, —C(S)O—,        —OC(S)NR_(b)—, —NR_(b)C(S)O—, —S—S—, and —S(O)₀₋₂—;    -   G_(6a) and G_(6b) are independently a chemical bond or C₁₋₅        alkylene, which is optionally substituted with 1, 2, 3 or 4 R**;    -   G_(6a) and G_(6b) have a total length of 0, 1, 2, 3, 4 or 5        carbon atoms;    -   R₉ and R** are independently H, C₁₋₆ alkyl, -L_(c)-OR_(c) or        -L_(c)-NR_(c)R′_(c);    -   one of L₃ and L₅, or one of L₄ and L₆ is —(CR^(s)R^(s′))₂—,        —CH═CH—, —C≡C—, and the other is a chemical bond;    -   G_(1a), G_(1b), G₂a, G₂b, G_(3a), G_(3b), G_(4a) and G_(4b) are        independently a chemical bond or C₁₋₇ alkylene, which is        optionally substituted with 1, 2, 3, 4 or 5 R^(s);    -   G_(1a), G_(1b), G_(2a) and G_(2b) have a total length of 1, 2,        3, 4, 5, 6 or 7 carbon atoms;    -   G_(3a), G_(3b), G_(4a) and G_(4b) have a total length of 1, 2,        3, 4, 5, 6 or 7 carbon atoms;    -   R₃ and R₄ are independently H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, 3- to        10-membered cycloalkyl or 3- to 10-membered heterocyclyl, which        is optionally substituted with 1, 2, 3, 4 or 5 R*;    -   or, R₃ and R₄ are taken together with the N atom to which they        are attached to form 3- to 10-membered heterocyclyl, which is        optionally substituted with 1, 2, 3, 4 or 5 R*;    -   or, R₄ and R₉ are taken together with the atoms to which they        are attached to form 3- to 10-membered heterocyclyl, which is        optionally substituted with 1, 2, 3 or 4 R*;    -   R* is independently H, halogen, cyano, C₁₋₆ alkyl, C₁₋₆        haloalkyl, -L_(b)-OR_(b) or -L_(b)-NR_(b)R′_(b);    -   R₅, R₆, R₇ and R₈ are independently C₁₋₆ alkyl, which is        optionally substituted with 1, 2, 3, 4 or 5 R*;    -   Y₁ and Y₂ are independently O, S or NR_(a);    -   L₁ and L₂ are independently —(CRR′)₂—, —CH═CH—, —C≡C— or —NR″—;    -   G₇, G₈, G₉ and G₁₀ are independently a chemical bond or C₁₋₁₂        alkylene, which is optionally substituted with 1, 2, 3, 4, 5 or        6 R;    -   G₇ and G₈ have a total length of 4, 5, 6, 7, 8, 9, 10, 11 or 12        carbon atoms;    -   G₉ and G₁₀ have a total length of 4, 5, 6, 7, 8, 9, 10, 11 or 12        carbon atoms;    -   1, 2 or 3 methylenes in G₇, G₈, G₉ or G₁₀ are optionally and        independently substituted with 1 R;    -   R^(s) and R^(s′) are independently H, C₁₋₁₀ alkyl, -L_(d)-OR_(d)        or -L_(d)-NR_(d)R′_(d);    -   R and R′ are independently H, C₁₋₁₄ alkyl, -L_(a)-OR_(a) or        -L_(a)-NR_(a)R′_(a);    -   R″ is independently H or C₁₋₁₄ alkyl;    -   L_(a) is independently a chemical bond or C₁₋₁₄ alkylene;    -   L_(b) is independently a chemical bond or C₁₋₆ alkylene;    -   L_(c) is independently a chemical bond or C₁₋₆ alkylene;    -   L_(d) is independently a chemical bond or C₁₋₁₀ alkylene;    -   R_(a) and R′_(a) are independently H, C₁₋₁₄ alkyl, 3- to        10-membered cycloalkyl or 3- to 10-membered heterocyclyl;    -   R_(b) and R′_(b) are independently H, C₁₋₆ alkyl, 3- to        10-membered cycloalkyl or 3- to 10-membered heterocyclyl;    -   R_(e) and R′_(e) are independently H or C₁₋₆ alkyl;    -   R_(d) and R′_(a) are independently H or C₁₋₁₀ alkyl.

In a more specific embodiment, the present disclosure provides acompound of formula (V) described above, or a pharmaceuticallyacceptable salt, isotopic variant, tautomer or stereoisomer thereof,wherein,

-   -   Q is selected from —C(O)O—, —O—, —SC(O)O—, —OC(O)NH—,        —NHC(O)NH—, —OC(O)S—, —OC(O)O—, —NHC(O)O—, —OC(O)—, —SC(O)—,        —C(O)S—, —NH—, —C(O)NH—, —NHC(O)—, —NHC(O)S—, —SC(O)NH—, —C(O)—,        —OC(S)—, —C(S)O—, —OC(S)NH— and —NHC(S)O—;    -   G_(6a) is a chemical bond or C₁₋₄ alkylene, which is optionally        substituted with 1, 2, 3 or 4 R**;    -   G_(6b) is a chemical bond or C₁₋₂ alkylene, which is optionally        substituted with 1 or 2 R**;    -   G_(6a) and G_(6b) have a total length of 0, 1, 2, 3 or 4 carbon        atoms;    -   R₉ and R** are independently H or C₁₋₆ alkyl;    -   one of L₃ and L₅, or one of L₄ and L₆ is —(CHR^(s))₂—, —CH═CH—        or —C≡C—, and the other is a chemical bond;    -   G_(1a) and G_(3a) are independently a chemical bond or C₁₋₇        alkylene;    -   G_(1b) and G_(3b) are independently a chemical bond or C₁₋₃        alkylene;    -   G_(2a) and G_(4a) are independently a chemical bond or C₁₋₃        alkylene;    -   G_(2b) and G₄O are independently a chemical bond or C₁₋₄        alkylene;    -   G_(1a), G_(1b), G_(2a) and G_(2b) have a total length of 1, 2,        3, 4, 5, 6 or 7 carbon atoms;    -   G_(3a), G_(3b), G_(4a) and G₄O have a total length of 1, 2, 3,        4, 5, 6 or 7 carbon atoms;    -   R₃ and R₄ are independently H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, 3- to        7-membered cycloalkyl or 3- to 7-membered heterocyclyl, which is        optionally substituted with 1, 2, 3, 4 or 5 R*;    -   or, R₃ and R₄ are taken together with the N atom to which they        are attached to form 3- to 7-membered heterocyclyl, which is        optionally substituted with 1, 2, 3, 4 or 5 R*;    -   or, R₄ and R₉ are taken together with the atoms to which they        are attached to form 3- to 7-membered heterocyclyl, which is        optionally substituted with 1, 2, 3, 4 or 5 R*;    -   R* is independently H, halogen, cyano, C₁₋₆ alkyl, C₁₋₆        haloalkyl, -L_(b)-OR_(b) or -L_(b)-NR_(b)R′_(b);    -   R₅, R₆, R₇ and R₈ are independently C₁₋₆ alkyl;    -   Y₁ and Y₂ are independently O, S or NR_(a);    -   L₁ and L₂ are independently —(CHR)₂—, —CH═CH—, —C≡C— or —NR″—;    -   G₇ and G₉ are independently a chemical bond or C₁₋₆ alkylene;    -   G₈ and G₁₀ are independently C₁₋₁₀ alkylene;    -   G₇ and G₈ have a total length of 4, 5, 6, 7, 8, 9 or 10 carbon        atoms;    -   G₉ and G₁₀ have a total length of 4, 5, 6, 7, 8, 9 or 10 carbon        atoms;    -   1, 2 or 3 methylenes in G₇, G₈, G₉ or G₁₀ are optionally and        independently substituted with 1 R;    -   R^(s) is independently H or C₁₋₆ alkyl;    -   R is independently H or C₁₋₁₀ alkyl;    -   R″ is independently H or C₁₋₁₀ alkyl;    -   L_(b) is independently a chemical bond or C₁₋₆ alkylene;    -   R_(a) is independently H or C₁₋₁₀ alkyl;    -   R_(b) and R′_(b) are independently H or C₁₋₆ alkyl.

In a more specific embodiment, the present disclosure provides acompound of formula (V) described above, or a pharmaceuticallyacceptable salt, isotopic variant, tautomer or stereoisomer thereof,wherein,

-   -   Q is —C(O)O—, —O—, —SC(O)O—, —OC(O)NH—, —NHC(O)NH—, —OC(O)S—,        —OC(O)O— or —NHC(O)O—;    -   G_(6a) is a chemical bond or C₁₋₄ alkylene, alternatively a        chemical bond or C₁₋₄ linear alkylene;    -   G_(6b) is a chemical bond or methylene;    -   G_(6a) and G_(6b) have a total length of 0, 1, 2, 3 or 4 carbon        atoms;    -   R₉ is H;    -   one of L₃ and L₅, or one of L₄ and L₆ is —(CH₂)₂—, —CH═CH—, or        —C≡C—, and the other is a chemical bond;    -   G_(1a) and G_(3a) are independently a chemical bond, —CH₂—,        —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—, —(CH₂)₅— or —(CH₂)₆—;    -   G_(1b) and G_(3b) are a chemical bond;    -   G_(2a) and G_(4a) are a chemical bond;    -   G_(2b) and G_(4b) are independently a chemical bond, —CH₂—,        —(CH₂)₂— or —(CH₂)₃—;    -   G_(1a), G_(1b), G_(2a) and G_(2b) have a total length of 1, 2,        3, 4, 5 or 6 carbon atoms;    -   G_(3a), G_(3b), G_(4a) and G_(4b) have a total length of 1, 2,        3, 4, 5 or 6 carbon atoms;    -   R₃ and R₄ are independently C₁₋₆ alkyl, which is optionally        substituted with 1, 2 or 3 R*;    -   or, R₃ and R₄ are taken together with the N atom to which they        are attached to form 5- to 7-membered heterocyclyl, which is        optionally substituted with 1, 2, 3, 4 or 5 R*;    -   or, R₄ and R₉ are taken together with the atoms to which they        are attached to form 6-membered heterocyclyl, which is        optionally substituted with 1, 2, 3, 4 or 5 R*;    -   R* is independently H, C₁₋₆ alkyl, C₁₋₆ haloalkyl or —OR_(b);    -   R₅, R₆, R₇ and R₈ are independently C₁₋₃ alkyl;    -   Y₁ and Y₂ are independently O, S or NR_(a), alternatively O or        S;    -   L₁ and L₂ are independently —(CHR)₂—, —CH═CH—, —C≡C— or —NR″—;    -   G₇ and G₉ are independently a chemical bond or C₁₋₅ alkylene,        alternatively a chemical bond or C₁₋₅ linear alkylene;    -   G₈ and G₁₀ are independently C₁₋₈ alkylene, alternatively C₁₋₈        linear alkylene;    -   G₇ and G₈ have a total length of 4, 5, 6, 7, 8, 9, 10 carbon        atoms;    -   G₉ and G₁₀ have a total length of 4, 5, 6, 7, 8, 9, 10 carbon        atoms;    -   1 or 2 methylenes in G₇, G₈, G₉ or G₁₀ are optionally and        independently substituted with 1 R;    -   R is independently H or C₁₋₈ alkyl, alternatively H or C₁₋₈        linear alkyl;    -   R″ is independently H or C₇₋₉ alkyl, alternatively H or C₇₋₉        linear alkyl;    -   R_(a) is independently H or C₈₋₁₀ alkyl, alternatively H or        C₈₋₁₀ linear alkyl;    -   R_(b) is independently H or C₁₋₆ alkyl, alternatively H.

In a more specific embodiment, the present disclosure provides acompound of formula (V) described above, or a pharmaceuticallyacceptable salt, isotopic variant, tautomer or stereoisomer thereof,wherein,

-   -   Q is —C(O)O—, —O—, —SC(O)O—, —OC(O)NH—, —NHC(O)NH—, —OC(O)S—,        —OC(O)O— or —NHC(O)O—;    -   G_(6a) is a chemical bond, —CH₂—, —(CH₂)₂—, —(CH₂)₃— or        —(CH₂)₄—;    -   G_(6b) is a chemical bond or methylene;    -   G_(6a) and G_(6b) have a total length of 0, 1, 2, 3 or 4 carbon        atoms;    -   R₉ is H;    -   -G_(1a)-L₃-G_(1b)- or -G_(3a)-L₄-G_(3b)- is independently        selected from the following groups:    -   —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—, —(CH₂)₅—, —(CH₂)₆—, —(CH₂)₇—,        —(CH₂)₈—, —(CH₂)₃—CH═CH—, —(CH₂)₃—C≡C—, —(CH₂)₂—CH═CH— and        —(CH₂)₂—C≡C—;    -   G_(2a)-L₅-G_(2b)- or -G_(4a)-L₆-G_(4b)- is independently        selected from the following groups:    -   a chemical bond, —CH₂—, —(CH₂)₂—, —(CH₂)₃—, —CH═CH—CH₂—, —C≡C—        and —C—C—CH₂—;

-   -    have a total length of 4, 5, 6, 7, 8 or 9 carbon atoms;    -   R₃ is Me, —CH₂CH₃, —CH₂CH₂OH or —CH(CH₃)₂;    -   R₄ is Me;    -   or, R₃ and R₄ are taken together with the N atom to which they        are attached to form

-   -   or, R₄ and R₉ are taken together with the atoms to which they        are attached to form

-   -   R₅, R₆, R₇ and R₈ are Me;    -   Y₁ and Y₂ are independently O, S or NR_(a);    -   L₁ and L₂ are independently —(CHR)₂—, —CH═CH—, —C≡C— or —NR″—;    -   G₇ and G₉ are independently a chemical bond, —CH₂—, —(CH₂)₂—,        —(CH₂)₄— or —(CH₂)₅—;    -   G₈ and G₁₀ are independently —(CH₂)₂—, —(CH₂)₄—, —(CH₂)₆—,        —(CH₂)₇— or —(CH₂)₈—;    -   G₇ and G₈ have a total length of 4, 5, 6, 7, 8, 9, 10 carbon        atoms;    -   G₉ and G₁₀ have a total length of 4, 5, 6, 7, 8, 9, 10 carbon        atoms;    -   1 or 2 methylenes in G₇, G₈, G₉ or G₁₀ are optionally and        independently substituted with 1 R;    -   R is independently H, Me, —(CH₂)₃CH₃, —(CH₂)₄CH₃, —(CH₂)₅CH₃,        —(CH₂)₆CH₃ or —(CH₂)₇CH₃;    -   R″ is —(CH₂)₇CH₃;    -   R_(a) is independently H or —(CH₂)₈CH₃.

Alternatively,

is independently selected from the following groups:

-   -   —(CH₂)₃—C(CH₃)₂—, —(CH₂)₄—C(CH₃)₂—, —(CH₂)₅—C(CH₃)₂—,        —(CH₂)₆—C(CH₃)₂—, —(CH₂)₇—C(CH₃)₂—, —(CH₂)₈—C(CH₃)₂—,        —(CH₂)₃—CH═CH—C(CH₃)₂—, —(CH₂)₃—C—C—C(CH₃)₂—,        —(CH₂)₄—C(CH₃)₂—CH₂—, —(CH₂)₃—C(CH₃)₂—(CH₂)₂—,        —(CH₂)₂—C(CH₃)₂—(CH₂)₃—, —(CH₂)₂—CH═CH—C(CH₃)₂—CH₂—,        —(CH₂)₂—C(CH₃)₂—C—C—CH₂—, —(CH₂)₂—C(CH₃)₂—CH═CH—CH₂—,        —(CH₂)₂—C—C—C(CH₃)₂—CH₂— and —(CH₂)₃—C(CH₃)₂—C≡C—;    -   -G₇-L₁-G₈-H or -G₉-L₂-G₁₀-H is independently selected from the        following groups:    -   —(CH₂)₅CH₃, —(CH₂)₆CH₃, —(CH₂)₇CH₃, —(CH₂)₈CH₃, —(CH₂)₉CH₃,        —(CH₂)₁₀CH₃, —(CH₂)₁₁CH₃, —CH₂—C≡C—(CH₂)₅CH₃,        —CH₂—C≡C—(CH₂)₆CH₃, —(CH₂)₂—C≡C—(CH₂)₅CH₃,        —(CH₂)₄—C≡C—(CH₂)₃CH₃, —CH₂—CH═CH—(CH₂)₅CH₃,        —CH₂—CH═CH—(CH₂)₆CH₃, —(CH₂)₂—CH═CH—(CH₂)₅CH₃,        —(CH₂)₄—CH═CH—(CH₂)₃CH₃, —(CH₂)₅—CH═CH—CH₂CH₃,

In a more specific embodiment, the present disclosure provides acompound of formula (VI) or formula (VII) described above, or apharmaceutically acceptable salt, isotopic variant, tautomer orstereoisomer thereof, wherein,

-   -   a, a′, b and g are independently 0, 1, 2, 3, 4 or 5, a′ and b        are not 0 at the same time;    -   a′+g=0, 1, 2, 3, 4 or 5;    -   c and e are independently 3, 4, 5, 6, 7, 8 or 9;    -   d and f are independently 0, 1, 2, 3 or 4;    -   c+d=3, 4, 5, 6, 7, 8 or 9, e+f=3, 4, 5, 6, 7, 8 or 9;    -   methylenes in

-   -    are optionally and independently substituted with 1, 2, 3, 4 or        5 C₁₋₆ alkyl;    -   R₃ and R₄ are independently H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, 3- to        10-membered cycloalkyl or 3- to 10-membered heterocyclyl, which        is optionally substituted with 1, 2, 3, 4 or 5 R*;    -   or, R₃ and R₄ are taken together with the N atom to which they        are attached to form 3- to 10-membered heterocyclyl, which is        optionally substituted with 1, 2, 3, 4 or 5 R*;    -   R* is independently H, halogen, cyano, C₁₋₆ alkyl, C₁₋₆        haloalkyl, -L_(b)-OR_(b) or -L_(b)-NR_(b)R′_(b);    -   R₅, R₆, R₇ and R₈ are independently C₁₋₆ alkyl, which is        optionally substituted with 1, 2, 3, 4 or 5 R*;    -   Y₁ and Y₂ are independently O, S or NR_(a);    -   L₁ and L₂ are independently —(CRR′)₂—, —CH═CH—, —C≡C— or —NR″—;    -   G₇, G₈, G₉ and G₁₀ are independently a chemical bond or C₁₋₁₂        alkylene, which is optionally substituted with 1, 2, 3, 4, 5 or        6 R;    -   G₇ and G₈ have a total length of 6, 7, 8, 9, 10, 11 or 12 carbon        atoms;    -   G₉ and G₁₀ have a total length of 6, 7, 8, 9, 10, 11 or 12        carbon atoms;    -   1, 2 or 3 methylenes in G₇, G₈, G₉ or G₁₀ are optionally and        independently substituted with 1 R;    -   R and R′ are independently H, C₁₋₁₄ alkyl, -L_(a)-OR_(a) or        -L_(a)-NR_(a)R′_(a);    -   L_(a) is independently a chemical bond or C₁₋₁₄ alkylene;    -   L_(b) is independently a chemical bond or C₁₋₆ alkylene;    -   R_(a) and R′_(a) are independently H, C₁₋₁₄ alkyl, 3- to        10-membered cycloalkyl or 3- to 10-membered heterocyclyl;    -   R_(b) and R′_(b) are independently H, C₁₋₆ alkyl, 3- to        10-membered cycloalkyl or 3- to 10-membered heterocyclyl;    -   R″ is independently H or C₁₋₁₄ alkyl.

In a more specific embodiment, the present disclosure provides acompound of formula (VI) or formula (VII) described above, or apharmaceutically acceptable salt, isotopic variant, tautomer orstereoisomer thereof, wherein,

-   -   a is 0, 1, 2, 3 or 4, alternatively 1, 2, 3 or 4, alternatively        2, 3 or 4;    -   a′ and b are independently 0, 1, 2, 3 or 4, alternatively 2;    -   g is 0, 1 or 2, alternatively 0 or 1;    -   a′+g=0, 1, 2, 3, 4 or 5, alternatively a′+g=2 or 3;    -   c and e are independently 3, 4, 5 or 6;    -   d and f are independently 0, 1 or 2;    -   c+d=4, 5 or 6, e+f=4, 5 or 6;    -   methylenes in

-   -    are optionally and independently substituted with 1, 2, 3, 4 or        5 C₁₋₆ alkyl;    -   methylenes in

-   -    are optionally and independently substituted with 1 or 2 C₁₋₆        alkyl;    -   R₃ and R₄ are independently C₁₋₆ alkyl, which is optionally        substituted with 1, 2 or 3 R*;    -   R* is independently H, C₁₋₆ alkyl, C₁₋₆ haloalkyl or —OR_(b);    -   or, R₃ and R₄ are taken together with the N atom to which they        are attached to form 3- to 7-membered heterocyclyl,        alternatively 5-membered heterocyclyl, which is optionally        substituted with 1, 2 or 3 R*;    -   R₅, R₆, R₇ and R₈ are independently C₁₋₆ alkyl, which is        optionally substituted with 1, 2, 3, 4 or 5 R*;    -   Y₁ and Y₂ are independently O, S or NR_(a), alternatively O or        S;    -   L₁ and L₂ are independently —(CHR)₂—, —CH═CH—, —C≡C— or —NR″—,        alternatively —(CHR)₂—, —CH═CH— or —C≡C—;    -   G₇ and G₉ are independently a chemical bond or C₁₋₆ alkylene;    -   G₈ and G₁₀ are independently C₁₋₁₀ alkylene;    -   G₇ and G₈ have a total length of 6, 7, 8, 9 or 10 carbon atoms;    -   G₉ and G₁₀ have a total length of 6, 7, 8, 9 or 10 carbon atoms;    -   1, 2 or 3 methylenes in G₇, G₈, G₉ or G₁₀ are optionally and        independently substituted with 1 R, alternatively the methylene        collected to Y₁ and Y₂ is not substituted with R;    -   R is independently H or C₁₋₈ alkyl;    -   R″ is independently H or C₁₋₁₀ alkyl;    -   R_(a) is independently H or C₁₋₁₀ alkyl;    -   R_(b) is independently H or C₁₋₆ alkyl, alternatively H.

In a more specific embodiment, the present disclosure provides acompound of formula (VI) described above, or a pharmaceuticallyacceptable salt, isotopic variant, tautomer or stereoisomer thereof,wherein,

-   -   a is 0, 1, 2, 3 or 4, alternatively 1, 2, 3 or 4, alternatively        2, 3 or 4;    -   c and e are independently 3, 4, 5 or 6;    -   d and f are independently 0, 1 or 2;    -   c+d=4, 5 or 6, e+f=4, 5 or 6;    -   R₃ and R₄ are independently C₁₋₆ alkyl;    -   or, R₃ and R₄ are taken together with the N atom to which they        are attached to form 4- to 6-membered heterocyclyl,        alternatively 5-membered heterocyclyl, which is optionally        substituted with 1, 2 or 3 R*;    -   R* is independently H, C₁₋₆ alkyl or C₁₋₆ haloalkyl;    -   R₅, R₆, R₇ and R₈ are independently C₁₋₆ alkyl, which is        optionally substituted with 1, 2, 3, 4 or 5 R*, alternatively        C₁₋₃ alkyl;    -   Y₁ and Y₂ are independently O, S or NR_(a), alternatively O or        S;    -   L₁ and L₂ are independently —(CHR)₂—, —CH═CH—, —C≡C— or —NR″—,        alternatively —(CHR)₂—, —CH═CH— or —C≡C—;    -   G₇ and G₉ are independently a chemical bond or C₁₋₅ alkylene,        alternatively a chemical bond or C₁₋₅ linear alkylene;    -   G₈ and G₁₀ are independently C₁₋₈ alkylene, alternatively C₁₋₈        linear alkylene;    -   G₇ and G₈ have a total length of 6, 7, 8, 9 or 10 carbon atoms;    -   G₉ and G₁₀ have a total length of 6, 7, 8, 9 or 10 carbon atoms;    -   1, 2 or 3 methylenes in G₇, G₈, G₉ or G₁₀ are optionally and        independently substituted with 1 R, alternatively the methylene        collected to Y₁ and Y₂ is not substituted with R;    -   R is independently H or C₁₋₈ alkyl, alternatively H or C₁₋₇        alkyl, alternatively H or C₁₋₆ alkyl;    -   R″ is independently H or C₇₋₉ alkyl;    -   R_(a) is independently H or C₈₋₁₀ alkyl.

Alternatively, R is independently H or C₁₋₈ linear alkyl, alternativelyH or C₁₋₇ linear alkyl, alternatively H or C₁₋₆ linear alkyl.

Alternatively, R″ is independently H or C₇₋₉ linear alkyl.

Alternatively, R_(a) is independently H or C₈₋₁₀ linear alkyl.

In a more specific embodiment, the present disclosure provides acompound of formula (VI) described above, or a pharmaceuticallyacceptable salt, isotopic variant, tautomer or stereoisomer thereof,wherein,

-   -   a is selected from 0, 1, 2, 3 or 4, alternatively 1, 2, 3 or 4,        alternatively 2, 3 or 4;    -   c and e are independently 3, 4, 5 or 6;    -   d and f are independently 0, 1 or 2;    -   c+d=4, 5 or 6, e+f=4, 5 or 6; alternatively,

-   -    are independently —(CH₂)₄—C(CH₃)₂—, —(CH₂)₅—C(CH₃)₂—,        —(CH₂)₆—C(CH₃)₂—, —(CH₂)₄—C(CH₃)₂—CH₂— or        —(CH₂)₃—C(CH₃)₂—(CH₂)₂—;    -   R₃ and R₄ are independently C₁₋₆ alkyl, alternatively Me;    -   or, R₃ and R₄ are taken together with the N atom to which they        are attached to form

-   -    alternatively

-   -   R₅, R₆, R₇ and R₈ are Me;    -   Y₁ and Y₂ are independently O, S or NR_(a), alternatively O or        S;    -   L₁ and L₂ are independently —(CHR)₂—, —CH═CH—, —C≡C— or —NR″—,        alternatively —(CHR)₂—, —CH═CH— or —C≡C—;    -   G₇ and G₉ are independently a chemical bond, —CH₂—, —(CH₂)₂—,        —(CH₂)₄— or —(CH₂)₅—;    -   G₈ and G₁₀ are independently —(CH₂)₂—, —(CH₂)₄—, —(CH₂)₆—,        —(CH₂)₇— or —(CH₂)₈—;    -   G₇ and G₈ have a total length of 6, 7, 8, 9, 10 carbon atoms;    -   G₉ and G₁₀ have a total length of 6, 7, 8, 9, 10 carbon atoms;    -   1, 2 or 3 methylenes in G₇, G₈, G₉ or G₁₀ are optionally and        independently substituted with 1 R, alternatively the methylene        collected to Y₁ and Y₂ is not substituted with R;    -   R is independently H, Me, —(CH₂)₃CH₃, —(CH₂)₄CH₃, —(CH₂)₅CH₃,        —(CH₂)₆CH₃ or —(CH₂)₇CH₃, alternatively H, Me, —(CH₂)₃CH₃,        —(CH₂)₄CH₃, —(CH₂)₅CH₃ or —(CH₂)₆CH₃, alternatively H, Me,        —(CH₂)₃CH₃, —(CH₂)₄CH₃ or —(CH₂)₅CH₃;    -   R_(a) is independently H or —(CH₂)₈CH₃;    -   R″ is —(CH₂)₇CH₃.

Alternatively, -G₇-L₁-G₈-H or -G₉-L₂-G₁₀-H is independently selectedfrom the following groups:

-   -   —(CH₂)₇CH₃, —(CH₂)₈CH₃, —(CH₂)₉CH₃, —(CH₂)₁₁CH₃,        —CH₂—C≡C—(CH₂)₅CH₃, —CH₂—C≡C—(CH₂)₆CH₃, —(CH₂)₂—C≡C—(CH₂)₅CH₃,        —(CH₂)₄—C≡C—(CH₂)₃CH₃, —CH₂—CH═CH—(CH₂)₆CH₃,        —(CH₂)₂—CH═CH—(CH₂)₅CH₃, —(CH₂)₄—CH═CH—(CH₂)₃CH₃,        —(CH₂)₅—CH═CH—CH₂CH₃

-   -    and alternatively is not

In a more specific embodiment, the present disclosure provides acompound of formula (VI) described above, or a pharmaceuticallyacceptable salt, isotopic variant, tautomer or stereoisomer thereof,wherein,

-   -   a is 2, 3 or 4;    -   c and e are independently 3, 4, 5 or 6;    -   d and f are independently 0, 1 or 2;    -   c+d=4, 5 or 6, e+f=4, 5 or 6;    -   R₃ and R₄ are independently C₁₋₆ alkyl, alternatively C₁₋₃        alkyl;    -   R₅, R₆, R₇ and R₈ are independently C₁₋₆ alkyl, alternatively        C₁₋₃ alkyl;    -   Y₁ and Y₂ are independently O or S;    -   L₁ and L₂ are independently —(CHR)₂—, —CH═CH— or —C≡C—;    -   G₇ and G₉ are independently C₁₋₄ alkylene, alternatively C₁₋₄        linear alkylene;    -   G₈ and G₁₀ are independently C₂₋₇ alkylene, alternatively C₂₋₇        linear alkylene;    -   G₇ and G₈ have a total length of 6, 7 or 8 carbon atoms;    -   G₉ and G₁₀ have a total length of 6, 7 or 8 carbon atoms;    -   1, 2 or 3 methylenes in G₇, G₈, G₉ or G₁₀ are optionally and        independently substituted with 1 R;    -   R is independently H or C₁₋₇ alkyl, alternatively H or C₁₋₇        linear alkyl;    -   provided that, when L₁ is —C≡C—, then G₇ is C₁₋₂ alkylene,        alternatively C₁₋₂ linear alkylene; and when L₂ is —C≡C—, then        G₉ is C₁₋₂ alkylene, alternatively C₁₋₂ linear alkylene.

Alternatively, the methylene collected to Y₁ and Y₂ is not substitutedwith R.

In a more specific embodiment, the present disclosure provides acompound of formula (VI) described above, or a pharmaceuticallyacceptable salt, isotopic variant, tautomer or stereoisomer thereof,wherein,

-   -   a is 2, 3 or 4;    -   c and e are independently 3, 4, 5 or 6;    -   d and f are independently 0, 1 or 2;    -   c+d=4, 5 or 6, e+f=4, 5 or 6; alternatively,

-   -    are independently —(CH₂)₄—C(CH₃)₂—, —(CH₂)₅—C(CH₃)₂—,        —(CH₂)₆—C(CH₃)₂—, —(CH₂)₄—C(CH₃)₂—CH₂— or        —(CH₂)₃—C(CH₃)₂—(CH₂)₂—;    -   R₃ and R₄ are independently C₁₋₆ alkyl, alternatively Me;    -   R₅, R₆, R₇ and R₈ are independently C₁₋₆ alkyl, alternatively        Me;    -   Y₁ and Y₂ are independently O or S;    -   L₁ and L₂ are independently —(CHR)₂—, —CH═CH— or —C≡C—;    -   G₇ and G₉ are independently —CH₂—, —(CH₂)₂— or —(CH₂)₄—;    -   G₈ and G₁₀ are independently —(CH₂)₄—, —(CH₂)₆— or —(CH₂)₇—;    -   G₇ and G₈ have a total length of 6, 7 or 8 carbon atoms;    -   G₉ and G₁₀ have a total length of 6, 7 or 8 carbon atoms;    -   1, 2 or 3 methylenes in G₇, G₈, G₉ or G₁₀ are optionally and        independently substituted with 1 R;    -   R is independently H, Me, —(CH₂)₃CH₃, —(CH₂)₄CH₃, —(CH₂)₅CH₃ or        —(CH₂)₆CH₃;    -   provided that, when L₁ is —C≡C—, then G₇ is —CH₂— or —(CH₂)₂—,        and when L₂ is —C≡C—, then G₉ is —CH₂— or —(CH₂)₂—;    -   alternatively, -G₇-L₁-G₈-H or -G₉-L₂-G₁₀-H is independently        selected from the following groups:    -   —(CH₂)₇CH₃, —(CH₂)₈CH₃, —(CH₂)₉CH₃, —CH₂—C≡C—(CH₂)₅CH₃,        —CH₂—C≡C—(CH₂)₆CH₃, —(CH₂)₂—C≡C—(CH₂)₅CH₃, —CH₂—CH═CH—(CH₂)₆CH₃,        —(CH₂)₂—CH═CH—(CH₂)₅CH₃, —(CH₂)₄—CH═CH—(CH₂)₃CH₃,

In a more specific embodiment, the present disclosure provides acompound of formula (VI) described above, or a pharmaceuticallyacceptable salt, isotopic variant, tautomer or stereoisomer thereof,wherein,

-   -   a is 2, 3 or 4, alternatively 2 or 3;    -   c and e are independently 4, 5 or 6;    -   d and f are 0;    -   R₃ and R₄ are independently C₁₋₆ alkyl, alternatively C₁₋₃        alkyl;    -   R₅, R₆, R₇ and R₈ are independently C₁₋₆ alkyl, alternatively        C₁₋₃ alkyl;    -   Y₁ and Y₂ are O;    -   L₁ and L₂ are independently —(CHR)₂— or —CH═CH—;    -   G₇ and G₉ are independently —CH₂— or —CH₂CHR—;    -   G₈ and G₁₀ are independently —(CH₂)₆— or —(CH₂)₇—;    -   G₇ and G₈ have a total length of 7 or 8 carbon atoms;    -   G₉ and G₁₀ have a total length of 7 or 8 carbon atoms;    -   1, 2 or 3 methylenes in G₈ or G₁₀ are optionally and        independently substituted with 1 R;    -   R is independently H or C₄₋₆ alkyl, alternatively H or C₅ alkyl;    -   alternatively -G₇-L₁-G₈-H and -G₉-L₂-G₁₀-H are not —(CH₂)₉CH₃ at        the same time.

Alternatively, R is independently H or C₄₋₆ linear alkyl, alternativelyH or C₅ linear alkyl.

In a more specific embodiment, the present disclosure provides acompound of formula (VI) described above, or a pharmaceuticallyacceptable salt, isotopic variant, tautomer or stereoisomer thereof,wherein,

-   -   a is 2, 3 or 4, alternatively 2 or 3;    -   c and e are independently 4, 5 or 6;    -   d and f are 0;    -   R₃ and R₄ are Me;    -   R₅, R₆, R₇ and R₈ are Me;    -   Y₁ and Y₂ are O;    -   -G₇-L₁-G₈-H and -G₉-L₂-G₁₀-H are independently selected from the        following groups:    -   —(CH₂)₈CH₃, —(CH₂)CH₃, —CH₂—CH═CH—(CH₂)₆CH₃,        —(CH₂)₂—CH═CH—(CH₂)₅CH₃,

-   -    alternatively —(CH₂)₈CH₃—(CH₂)₉CH₃, —CH₂—CH═CH—(CH₂)₆CH₃,        —(CH₂)₂—CH═CH—(CH₂)₅CH₃ and

-   -    alternatively    -   -G₇-L₁-G₈-H and -G₉-L₂-G₁₀-H are not —(CH₂)₉CH₃ at the same        time.

In a more specific embodiment, the present disclosure provides acompound of formula (VI) described above, or a pharmaceuticallyacceptable salt, isotopic variant, tautomer or stereoisomer thereof,wherein,

-   -   a is 3;    -   c and e are independently 5 or 6, alternatively 6;    -   d and f are 0;    -   R₃ and R₄ are independently C₁₋₃ alkyl;    -   R₅, R₆, R₇ and R₈ are independently C₁₋₃ alkyl;    -   Y₁ and Y₂ are O;    -   L₁ and L₂ are independently —(CHR)₂— or —CH═CH, alternatively        —(CHR)₂—;    -   G₇ and G₉ are independently —CH₂— or —CH₂CHR—;    -   G₈ and G₁₀ are independently —(CH₂)₆— or —(CH₂)₇—;    -   G₇ and G₈ have a total length of 7 or 8 carbon atoms,        alternatively 7 carbon atoms;    -   G₉ and G₁₀ have a total length of 7 or 8 carbon atoms,        alternatively 7 carbon atoms;    -   1, 2 or 3 methylenes in G₈ or G₁₀ are optionally and        independently substituted with 1 R;    -   R is independently H or C₄₋₆ alkyl, alternatively H or C₅ alkyl.

Alternatively, R is independently H or C₄₋₆ linear alkyl, alternativelyH or C₅ linear alkyl.

In a more specific embodiment, the present disclosure provides acompound of formula (VI) described above, or a pharmaceuticallyacceptable salt, isotopic variant, tautomer or stereoisomer thereof,wherein,

-   -   a is 3;    -   c and e are 6;    -   d and f are 0;    -   R₃ and R₄ are Me;    -   R₅, R₆, R₇ and R₈ are Me;    -   Y₁ and Y₂ are O;    -   -G₇-L₁-G₈-H and -G₉-L₂-G₁₀-H are independently selected from the        following groups:    -   —(CH₂)₈CH₃,

-   -    alternatively —(CH₂)₈CH₃ and

In a more specific embodiment, the present disclosure provides acompound of formula (VI) described above, or a pharmaceuticallyacceptable salt, isotopic variant, tautomer or stereoisomer thereof,wherein,

-   -   a is 2 or 3, alternatively 2;    -   c and e are independently 4, 5 or 6, alternatively 5;    -   d and f are 0;    -   R₃ and R₄ are independently C₁₋₃ alkyl;    -   R₅, R₆, R₇ and R₈ are independently C₁₋₃ alkyl;    -   one of Y₁ and Y₂ is O, and the other is S;    -   L₁ and L₂ are independently —(CHR)₂— or —CH═CH, alternatively        —(CHR)₂—;    -   G₇ and G₉ are independently —CH₂— or —CH₂CHR—;    -   G₈ and G₁₀ are independently —(CH₂)₅— or —(CH₂)₆—;    -   G₇ and G₈ have a total length of 7 carbon atoms;    -   G₉ and G₁₀ have a total length of 7 carbon atoms;    -   1, 2 or 3 methylenes in G₈ or G₁₀ are optionally and        independently substituted with 1 R;    -   R is independently H or C₄₋₆ alkyl, alternatively H or C₅ alkyl.

Alternatively, R is independently H or C₄₋₆ linear alkyl, alternativelyH or C₅ linear alkyl.

In a more specific embodiment, the present disclosure provides acompound of formula (VI) described above, or a pharmaceuticallyacceptable salt, isotopic variant, tautomer or stereoisomer thereof,wherein,

-   -   a is 2;    -   c and e are 5;    -   d and f are 0;    -   R₃ and R₄ are Me;    -   R₅, R₆, R₇ and R₈ are Me;    -   one of Y₁ and Y₂ is O, and the other is S;    -   -G₇-L₁-G₈-H and -G₉-L₂-G₁₀-H are independently selected from the        following groups.    -   —(CH₂)₈CH₃,

-   -    alternatively —(CH₂)₈CH₃.

In a more specific embodiment, the present disclosure provides acompound of formula (VI) described above, or a pharmaceuticallyacceptable salt, isotopic variant, tautomer or stereoisomer thereof,wherein,

-   -   a are 2;    -   c and e are independently 4, 5 or 6, alternatively 5;    -   d and f are 0;    -   R₃ and R₄ are independently C₁₋₆ alkyl, alternatively C₁₋₃        alkyl;    -   R₅, R₆, R₇ and R₈ are independently C₁₋₆ alkyl, alternatively        C₁₋₃ alkyl;    -   Y₁ and Y₂ are independently O or S;    -   one of L₁ and L₂ is —C≡C—, the other is —(CHR)₂—, or both of L₁        and L₂ are —C≡C—; alternatively one of L₁ and L₂ is —C≡C—, the        other is —(CHR)₂—;    -   G₇ and G₉ are —CH₂—;    -   G₈ and G₁₀ are independently —(CH₂)₆— or —(CH₂)₇—;    -   1 methylene in G₈ or G₁₀ optionally and independently        substituted with 1 R, alternatively G₈ and G₁₀ are independently        —CHR—(CH₂)₅—, —CHR—(CH₂)₆—, —CH₂—CHR—(CH₂)₄— or        —(CH₂)₂—CHR—(CH₂)₄—;    -   R is independently H or C₄₋₆ alkyl, alternatively H or C₅ alkyl;    -   provided that, only one of the -G₇-L₁-G₈-H and -G₉-L₂-G₁₀-H is        substituted with one non-hydrogen R substituent and the other is        unsubstituted.

Alternatively, R is independently H or C₄₋₆ linear alkyl, alternativelyH or C₅ linear alkyl.

In a more specific embodiment, the present disclosure provides acompound of formula (VI) described above, or a pharmaceuticallyacceptable salt, isotopic variant, tautomer or stereoisomer thereof,wherein,

-   -   a is 2;    -   c and e are 5;    -   d and f are 0;    -   R₃ and R₄ are Me;    -   R₅, R₆, R₇ and R₈ are Me;    -   Y₁ and Y₂ are independently O or S;    -   -G₇-L₁-G₈-H and -G₉-L₂-G₁₀-H are independently selected from the        following groups:

—(CH₂)₈CH₃, —(CH₂)₉CH₃, —CH₂—C≡C—(CH₂)₆CH₃,

-   -   provided that, at least one of -G₇-L₁-G₈-H and -G₉-L₂-G₁₀-H        comprises alkynyl, and one of the two has a substituent while        the other one has no substituent.

In a more specific embodiment, the present disclosure provides acompound of formula (VI) described above, or a pharmaceuticallyacceptable salt, isotopic variant, tautomer or stereoisomer thereof,wherein,

-   -   a is 2;    -   c and e are independently 4, 5 or 6, alternatively 5;    -   d and f are 0;    -   R₃ and R₄ are independently C₁₋₃ alkyl, alternatively Me;    -   R₅, R₆, R₇ and R₈ are independently C₁₋₃ alkyl, alternatively        Me;    -   Y₁ and Y₂ are independently O or S, alternatively 0;    -   both of L₁ and L₂ are —C≡C—;    -   G₇ and G₉ are —CH₂—;    -   G₈ and G₁₀ are independently —(CH₂)₆— or —(CH₂)₇—, alternatively        —(CH₂)₇—.

In a more specific embodiment, the present disclosure provides acompound of formula (VI) described above, or a pharmaceuticallyacceptable salt, isotopic variant, tautomer or stereoisomer thereof,wherein,

-   -   a is 2;    -   c and e are 3;    -   d and f are 2;    -   R₃ and R₄ are independently C₁₋₃ alkyl, alternatively Me;    -   R₅, R₆, R₇ and R₈ are independently C₁₋₃ alkyl;    -   Y₁ and Y₂ are independently O or S, alternatively 0;    -   L₁ and L₂ are —(CHR)₂—;    -   G₇ and G₉ are independently —CH₂— or —CH₂CHR—;    -   G₈ and G₁₀ are independently —(CH₂)₅—, —(CH₂)₆— or —(CH₂)₇—;    -   G₇ and G₈ have a total length of 6, 7 or 8 carbon atoms,        alternatively 7 carbon atoms;    -   G₉ and G₁₀ have a total length of 6, 7 or 8 carbon atoms,        alternatively 7 carbon atoms;    -   1, 2 or 3 methylenes in G₈ or G₁₀ are optionally and        independently substituted with 1 R;    -   R is independently H or C₁₋₇ alkyl, alternatively H or C₁₋₆        alkyl, alternatively Me.

Alternatively, R is independently H or C₁₋₇ linear alkyl, alternativelyH or C₁₋₆ linear alkyl, alternatively Me.

In a more specific embodiment, the present disclosure provides acompound of formula (VI) described above, or a pharmaceuticallyacceptable salt, isotopic variant, tautomer or stereoisomer thereof,wherein,

-   -   a is 2;    -   c and e are 3;    -   d and f are 2;    -   R₃ and R₄ are Me;    -   R₅, R₆, R₇ and R₈ are Me;    -   Y₁ and Y₂ are independently O or S, alternatively 0;    -   -G₇-L₁-G₈-H and -G₉-L₂-G₁₀-H are independently selected from the        following groups:

-   -   alternatively

-   -   alternatively

In a more specific embodiment, the present disclosure provides acompound of formula (VI) described above, or a pharmaceuticallyacceptable salt, isotopic variant, tautomer or stereoisomer thereof,wherein,

-   -   a is 2;    -   c and e are 4, 5, or 6, alternatively 5;    -   d and f are 0;    -   R₃ and R₄ are independently C₁₋₆ alkyl, alternatively C₁₋₃        alkyl;    -   R₅, R₆, R₇ and R₈ are independently C₁₋₆ alkyl, alternatively        C₁₋₃ alkyl;    -   Y₁ and Y₂ are S;    -   L₁ and L₂ are —(CHR)₂—;    -   G₇ and G₉ are independently —CH₂— or —CH₂CHR—;    -   G₈ and G₁₀ are independently —(CH₂)₅—, —(CH₂)₆— or —(CH₂)₇—;    -   G₇ and G₈ have a total length of 7 or 8 carbon atoms,        alternatively 8 carbon atoms;    -   G₉ and G₁₀ have a total length of 7 or 8 carbon atoms,        alternatively 8 carbon atoms;    -   1, 2 or 3 methylenes in G₈ or G₁₀ are optionally and        independently substituted with 1 R;    -   R is independently H or C₄₋₆ alkyl, alternatively H or C₅ alkyl.

Alternatively, R is independently H or C₄₋₆ linear alkyl, alternativelyH or C₅ linear alkyl.

In a more specific embodiment, the present disclosure provides acompound of formula (VI) described above, or a pharmaceuticallyacceptable salt, isotopic variant, tautomer or stereoisomer thereof,wherein,

-   -   a is 2;    -   c and e are 5;    -   d and f are 0;    -   R₃ and R₄ are independently Me;    -   R₅, R₆, R₇ and R₈ are independently Me;    -   Y₁ and Y₂ are S;    -   -G₇-L₁-G₈-H and -G₉-L₂-G₁₀-H are independently selected from the        following.    -   —(CH₂)₈CH₃, —(CH₂)₉CH₃,

-   -    alternatively —(CH₂)₈CH₃ or —(CH₂)₉CH₃, alternatively        —(CH₂)₉CH₃.

In a more specific embodiment, the present disclosure provides acompound of formula (VII) described above, or a pharmaceuticallyacceptable salt, isotopic variant, tautomer or stereoisomer thereof,wherein,

-   -   a′ and b are 2;    -   g is 0 or 1;    -   c and e are 5;    -   d and f are 0;    -   R₃ is C₁₋₆ alkyl, which is optionally substituted with 1, 2 or 3        R*;    -   R* is independently H, C₁₋₆ alkyl, C₁₋₆ haloalkyl or —OR_(b),        alternatively H, C₁₋₆ alkyl or C₁₋₆ haloalkyl;    -   R₅, R₆, R₇ and R₈ are independently C₁₋₃ alkyl;    -   Y₁ and Y₂ are independently O or S;    -   L₁ and L₂ are —(CHR)₂—;    -   G₇ and G₉ are independently —CH₂— or —CH₂CHR—;    -   G₈ and G₁₀ are independently —(CH₂)₅—, —(CH₂)₆— or —(CH₂)₇—;    -   G₇ and G₈ have a total length of 6, 7 or 8 carbon atoms;    -   G₉ and G₁₀ have a total length of 6, 7 or 8 carbon atoms;    -   1, 2 or 3 methylenes in G₈ or G₁₀ are optionally and        independently substituted with 1 R;    -   R is independently H or C₄₋₆ alkyl;    -   R_(b) is independently H or C₁₋₆ alkyl, alternatively H.

Alternatively, R is independently H or C₄₋₆ linear alkyl.

In a more specific embodiment, the present disclosure provides acompound of formula (VII) described above, or a pharmaceuticallyacceptable salt, isotopic variant, tautomer or stereoisomer thereof,wherein,

-   -   a′ and b are 2;    -   g is 0 or 1;    -   c and e are 5;    -   d and f are 0;    -   R₃ is Me, —CH₂CH₃, —CH₂CH₂OH or —CH(CH₃)₂, alternatively Me,        —CH₂CH₃ or —CH(CH₃)₂;    -   R₅, R₆, R₇ and R₈ are independently Me;    -   Y₁ and Y₂ are independently O or S;    -   -G₇-L₁-G₈-H or -G₉-L₂-G₁₀-H is independently selected from the        following groups:    -   —(CH₂)₇CH₃, —(CH₂)₈CH₃, —(CH₂)₉CH₃,

-   -    alternatively —(CH₂)₇CH₃, —(CH₂)₈CH₃, —(CH₂)₉CH₃ and

In a more specific embodiment, the present disclosure provides acompound of formula (VII) described above, or a pharmaceuticallyacceptable salt, isotopic variant, tautomer or stereoisomer thereof,wherein,

-   -   R₃ is Me or —CH₂CH₃, alternatively Me;    -   Both of Y₁ and Y₂ are O;    -   G₇ and G₈ have a total length of 6 or 7 carbon atoms,        alternatively 7 carbon atoms;    -   G₉ and G₁₀ have a total length of 6 or 7 carbon atoms,        alternatively 7 carbon atoms.

In a more specific embodiment, the present disclosure provides acompound of formula (VII) described above, or a pharmaceuticallyacceptable salt, isotopic variant, tautomer or stereoisomer thereof,wherein,

-   -   a′ and b are 2;    -   g is 0 or 1;    -   c and e are 5;    -   d and f are 0;    -   R₃ is Me or —CH₂CH₃, alternatively Me;    -   R₅, R₆, R₇ and R₈ are independently Me;    -   both of Y₁ and Y₂ are O;    -   -G₇-L₁-G₈-H or -G₉-L₂-G₁₀-H is independently selected from the        following groups:    -   —(CH₂)₇CH₃, —(CH₂)₈CH₃,

-   -    alternatively —(CH₂)₇CH₃, —(CH₂)₈CH₃ and

-   -    alternatively is not —(CH₂)₇CH₃.

In a more specific embodiment, the present disclosure provides acompound of formula (VII) described above, or a pharmaceuticallyacceptable salt, isotopic variant, tautomer or stereoisomer thereof,wherein,

-   -   R₃ is Me or —CH₂CH₃;    -   Y₁ and Y₂ are independently O or S, where Y₁ and Y₂ are not O at        the same time;    -   G₇ and G₈ have a total length of 6, 7 or 8 carbon atoms;    -   G₉ and G₁₀ have a total length of 6, 7 or 8 carbon atoms.

In a more specific embodiment, the present disclosure provides acompound of formula (VII) described above, or a pharmaceuticallyacceptable salt, isotopic variant, tautomer or stereoisomer thereof,wherein,

-   -   g is 0 or 1, alternatively 1;    -   R₃ is Me or —CH₂CH₃, alternatively Me;    -   one of Y₁ and Y₂ is O, and the other is S;    -   G₇ and G₈ have a total length of 7 carbon atoms;    -   G₉ and G₁₀ have a total length of 7 carbon atoms.

In a more specific embodiment, the present disclosure provides acompound of formula (VII) described above, or a pharmaceuticallyacceptable salt, isotopic variant, tautomer or stereoisomer thereof,wherein,

-   -   a′ and b are 2;    -   g is 0 or 1, alternatively 1;    -   c and e are 5;    -   d and f are 0;    -   R₃ is Me or —CH₂CH₃, alternatively Me;    -   R₅, R₆, R₇ and R₈ are independently Me;    -   one of Y₁ and Y₂ is O, and the other is S;    -   -G₇-L₁-G₈-H or -G₉-L₂-G₁₀-H is independently selected from the        following groups:    -   —(CH₂)₈CH₃

-   -    alternatively —(CH₂)₈CH₃ and

In a more specific embodiment, the present disclosure provides acompound of formula (VII) described above, or a pharmaceuticallyacceptable salt, isotopic variant, tautomer or stereoisomer thereof,wherein,

-   -   g is 0 or 1, alternatively 0;    -   R₃ is Me or —CH₂CH₃;    -   both of Y₁ and Y₂ are S;    -   G₇ and G₈ have a total length of 7 or 8 carbon atoms;    -   G₉ and G₁₀ have a total length of 7 or 8 carbon atoms.

In a more specific embodiment, the present disclosure provides acompound of formula (VII) described above, or a pharmaceuticallyacceptable salt, isotopic variant, tautomer or stereoisomer thereof,wherein,

-   -   a′ and b are 2;    -   g is 0 or 1, alternatively 0;    -   c and e are 5;    -   d and f are 0;    -   R₃ is Me or —CH₂CH₃;    -   R₅, R₆, R₇ and R₈ are independently Me;    -   both of Y₁ and Y₂ are S;    -   -G₇-L₁-G₈-H or -G₉-L₂-G₁₀-H is independently selected from the        following groups:    -   —(CH₂)₈CH₃, —(CH₂)₉CH₃,

-   -    alternatively —(CH₂)₈CH₃, —(CH₂)₉CH₃ and

In a more specific embodiment, the present disclosure provides acompound of formula (IV) described above, or a pharmaceuticallyacceptable salt, isotopic variant, tautomer or stereoisomer thereof,wherein, the compound is selected from the following:

In a more specific embodiment, the present disclosure provides ananoparticle composition, comprising a lipid component, and optionallycomprising a load; wherein, the lipid component contains a compound ofthe present disclosure.

Alternatively, the lipid component comprises components in the followingmolar percentages:

-   -   any of the above compounds of the present disclosure: 50 mol %;    -   neutral lipids: 10 mol %;    -   structure lipids: 38.5 mol %;    -   polymer lipids: 1.5 mol %.

In a more specific embodiment, the present disclosure provides thenanoparticle composition described above, wherein, the neutral lipidsare selected from one or more of DSPC, DMPC, DOPC, DPPC, POPC, DOPE,DMPE, POPE and DPPE, alternatively DSPC and/or DOPE.

In a more specific embodiment, the present disclosure provides thenanoparticle composition described above, wherein, the structure lipidsare selected from one or more of cholesterol, sitosterol, coprosterol,fucosterol, brassicasterol, ergosterol, tomatine, ursolic acid,α-tocopherol, stigmasterol, avenasterol, ergocalciferol and campestero,alternatively cholesterol and/or β-sitosterol, more alternativelycholesterol.

In a more specific embodiment, the present disclosure provides thenanoparticle composition described above, wherein, the polymer lipidsare polyethylene glycolated lipids.

Optionally, the polyethylene glycolated lipids are selected from one ormore of: PEG modified phosphatidylethanolamine, PEG modifiedphosphatidic acid, PEG modified ceramide, PEG modified dialkyl amine,PEG modified diacylglycerol, and PEG modified dialkylglycerol.

Alternatively, the polyethylene glycolated lipids contain a PEG moietyof about 1000 Da to about 20 kDa, alternatively a PEG moiety of about1000 Da to about 5000 Da.

Alternatively, the polyethylene glycolated lipids are selected from oneor more of DMPE-PEG1000, DPPE-PEG1000, DSPE-PEG1000, DOPE-PEG1000,DMG-PEG2000, Ceramide-PEG2000, DMPE-PEG2000, DPPE-PEG2000, DSPE-PEG2000,Azido-PEG2000, DSPE-PEG2000-Mannose, Ceramide-PEG5000, and DSPE-PEG5000,alternatively DMG-PEG2000.

In a more specific embodiment, the present disclosure provides thenanoparticle composition described above, wherein, the load is one ormore of therapeutic, prophylactic or diagnostic agents;

-   -   alternatively, the therapeutic, prophylactic or diagnostic agent        is a nucleic acid;    -   alternatively, the nucleic acid is one or more of ASO, RNA or        DNA;    -   alternatively, the RNA is selected from one or more of        interfering RNA (RNAi), small interfering RNA (siRNA), short        hairpin RNA (shRNA), antisense RNA (aRNA), messenger RNA (mRNA),        modified messenger RNA (mmRNA), long non-coding RNA (lncRNA),        microRNA (miRNA), small activating RNA (saRNA), multimeric        coding nucleic acid (MCNA), polymeric coding nucleic acid        (PCNA), guide RNA (gRNA), CRISPRRNA (crRNA) and nucleases,        alternatively mRNA, more alternatively, modified mRNA.

In a more specific embodiment, the present disclosure also provides alipid compound, a pharmaceutically acceptable salt or stereoisomerthereof, the lipid compound having the structure of general formula (I):

-   -   wherein,    -   G₁, G₂, G₃ or G₄ is each independently a bond, C₁₋₂₀ alkylene,        C₂₋₂₀ alkenylene or C₂₋₂₀ alkynylene;    -   G₅ or G₆ is each independently a bond or C₁₋₈ alkylene;    -   M₁ or M₂ is each independently biodegradable groups;    -   Q is a bond or biodegradable groups;    -   R₁ or R₂ is each independently C₄₋₂₈ alkyl, C₄₋₂₈ alkenyl or        C₄₋₂₈ alkynyl;    -   R₃ or R₄ is each independently H, alkyl, alkenyl, alkynyl,        cycloalkyl, heterocyclyl, aryl or heteroaryl;    -   or, R₃ and R₄ are taken together with the N atom to which they        are attached to form 3- to 14-membered heterocyclyl;    -   R₅, R₆, R₇ or R₈ is each independently C₁₋₈ alkyl;    -   each of the alkyl, alkenyl, alkynyl, alkylene, alkenylene,        alkynylene, cycloalkyl, heterocyclyl, aryl or heteroaryl is each        independently and optionally further substituted.

Further, disclosed herein is the lipid compound, which has the structureof general formula (I).

-   -   wherein,    -   G₁, G₂, G₃ or G₄ is each independently a bond, C₁₋₂₀ alkylene,        C₂₋₂₀ alkenylene or C₂₋₂₀ alkynylene; the C₁₋₂₀ alkylene, C₂₋₂₀        alkenylene or C₂₋₂₀ alkynylene is optionally substituted with        one or more substituents selected from H, OH, alkyl,        hydroxyalkyl, alkoxy, amino, alkylamino, and dialkylamino;    -   G₅ or G₆ is each independently a bond or C₁₋₆ alkylene; the C₁₋₆        alkylene is optionally substituted with one or more substituents        selected from H, OH, alkyl, hydroxyalkyl, alkoxy, amino,        alkylamino, and dialkylamino;    -   M₁ or M₂ is each independently selected from —OC(O)—, —C(O)O—,        —SC(O)—, —C(O)S—, —O—, —OC(O)O—, —SC(O)O—, —OC(O)S—, —NR_(a)—,        —C(O)NR_(a)—, —NR_(a)C(O)—, —NR_(a)C(O)O—, —OC(O)NR_(a)—,        —NR_(a)C(O)S—, —SC(O)NR_(a)—, —NR_(a)C(O)NR_(a)—, —C(O)—,        —OC(S)—, —C(S)O—, —OC(S)NR_(a)—, —NR_(a)C(S)O—, —S—S— and        —S(O)_(m)—;    -   Q is selected from a bond, —OC(O)—, —C(O)O—, —SC(O)—, —C(O)S—,        —O—, —OC(O)O—, —SC(O)O—, —OC(O)S—, —NR_(b)—, —C(O)NR_(b)—,        —NR_(b)C(O)—, —NR_(b)C(O)O—, —OC(O)NR_(b)—, —NR_(b)C(O)S—,        —SC(O)NR_(b)—, —NR_(b)C(O)NR_(b)—, —C(O)—, —OC(S)—, —C(S)O—,        —OC(S)NR_(b)—, —NR_(a)C(S)O—, —S—S—, —S(O)_(n)—, phenylene and        pyridylidene; the phenylene or pyridylidene group is optionally        substituted with one or more substituents selected from H,        hydroxy, halogen, cyano, alkyl, hydroxyalkyl, haloalkyl and        alkoxy;    -   R₁ or R₂ is each independently C₄₋₂₈ alkyl, C₄₋₂₈ alkenyl or        C₄₋₂₈ alkynyl; the C₄₋₂₈ alkyl, C₄₋₂₈ alkenyl or C₄₋₂₈ alkynyl        is optionally substituted with one or more substituents selected        from H, OH, alkyl, hydroxyalkyl, alkoxy, amino, alkylamino, and        dialkylamino;    -   R₃ or R₄ is each independently H or C₁₋₂₀ alkyl; the C₁₋₂₀ alkyl        is optionally substituted with one or more substituents selected        from H, OH, alkyl, hydroxyalkyl, alkoxy, amino, alkylamino, and        dialkylamino;    -   or, R₃ and R₄ are taken together with the N atom to which they        are attached to form 3- to 14-membered heterocyclyl; the 3- to        14-membered heterocyclyl is optionally further substituted with        a substituent selected from halogen, cyano, OH, alkyl,        hydroxyalkyl, haloalkyl, alkoxy, amino, alkylamino, and        dialkylamino;    -   R₅, R₆, R₇ or R₈ is each independently C₁₋₈ alkyl;    -   each of R_(a) or R_(b) is each independently H, C₁₋₂₈ alkyl or        C₃₋₁₄ cycloalkyl; the C₁₋₂₈ alkyl or C₃₋₁₄ cycloalkyl is        optionally substituted with one or more substituents selected        from H, OH, alkyl, hydroxyalkyl, alkoxy, amino, alkylamino, and        dialkylamino;    -   m or n is each independently 0, 1 or 2.

Further, the G₁ and G₃ are both C₂₋₈ alkylene, and G₂ and G₄ are both abond; alternatively G₁ and G₃ are both C₅ alkylene, and G₂ and G₄ areboth a bond.

Further, the G₅ is a bond.

Further, the G₆ is a bond or C₁₋₆ alkylene.

Further, the M₁ or M₂ is each independently —C(O)O—, —OC(O)—, —C(O)S—,—SC(O)—, —NR_(a)C(O)— or —C(O)NR_(a)—, the R_(a) is H or C₄₋₂₄ alkyl;alternatively M₁ or M₂ is each independently —C(O)O— or —C(O)S—.

Further, the Q is a bond, —O—, —OC(O)—, —C(O)O—, —OC(O)O— or —OC(O)NH—,—NHC(O)O—, —NHC(O)NH—, —OC(O)S—, or —SC(O)O—; alternatively Q is—C(O)O—.

Further, the R₁ or R₂ is each independently C₄₋₂₈ alkyl, C₄₋₂₈ alkenylor C₄₋₂₈ alkynyl, the C₄₋₂₈ alkyl, C₄₋₂₈ alkenyl or C₄₋₂₈ alkynyl isoptionally substituted with one or more substituents H, hydroxyl orC₂₋₁₄ alkyl; alternatively R₁ or R₂ is each independently C₄₋₂₈ alkyl,C₄₋₂₈ alkenyl or C₄₋₂₈ alkynyl.

Further, the R₃ or R₄ is each independently C₁₋₆ alkyl or hydroxyethyl;alternatively R₃ or R₄ are both methyl.

Further, the R₅, R₆, R₇ or R₈ is each independently C₁₋₃ alkyl;alternatively R₅, R₆, R₇ or R₈ are both methyl.

Further, the lipid compound is the compounds of general formula (II) orgeneral formula (III):

-   -   wherein the substituents are defined as described in general        formula (I).

The present disclosure provides a lipid compound, a pharmaceuticallyacceptable salt or stereoisomer thereof, wherein the lipid compound isselected from the following compounds:

The present disclosure provides a composition, the composition comprisesa biologically active substance and lipid compounds of the presentdisclosure.

Further, the biologically active substance is DNA or RNA.

Further, the composition further comprises neutral lipids, structurelipids and polymeric lipids.

Further, the neutral lipids are DSPC, DMPC, DOPC, DPPC, POPC, DOPE,DMPE, POPE or DPPE.

Further, the structure lipids are selected from one of, or a combinationof cholesterol, sitosterol, coprosterol, fucosterol, brassicasterol,ergosterol, tomatine, ursolic acid, α-tocopherol, stigmasterol,avenasterol, ergocalciferol and campesterol.

Further, the polymeric lipids are selected from one of, or a combinationof DMPE-PEG1000, DPPE-PEG1000, DSPE-PEG1000, DOPE-PEG1000, DMG-PEG2000,Ceramide-PEG2000, DMPE-PEG2000, DPPE-PEG2000, DSPE-PEG2000,Azido-PEG2000, DSPE-PEG2000-Mannose, Ceramide-PEG5000, and DSPE-PEG5000.

The present disclosure provides a lipid nanoparticle comprising thelipid compound of the present disclosure or the composition of thepresent disclosure.

The present disclosure provides a pharmaceutical composition comprisingthe lipid compound of the present disclosure, the composition of thepresent disclosure or the lipid nanoparticle of the present disclosure,and pharmaceutically acceptable excipient(s).

The present disclosure provides the use of the lipid compound of thepresent disclosure, the composition of the present disclosure, the lipidnanoparticle of the present disclosure or the pharmaceutical compositionof the present disclosure in the manufacture of a medicament fortreating or preventing a disease.

The present disclosure provides a method for preparing the compound ofgeneral formula (II), comprising:

-   -   reacting the compound of general formula (IIb) with the compound        of general formula (IIc), to give the compound of general        formula (II);    -   wherein the substituents are defined as described in general        formula (I).

The present disclosure provides a compound, a pharmaceuticallyacceptable salt thereof or a stereoisomer thereof, the compound havingthe structure of general formula (IIa) or general formula (IIb):

-   -   wherein the substituents are defined as described in general        formula (I).

When the degradable group in the compound is changed, the compound ofthe corresponding structure can be prepared by the conventional methodsin the field such as esterification and amide condensation.

The present disclosure provides the use of the compounds having thestructure of general formula (IIa) or general formula (IIb),pharmaceutically acceptable salts or stereoisomers thereof in thepreparation of cationic lipids.

The present disclosure also provides a lipid compound, apharmaceutically acceptable salt, or a stereoisomer thereof, the lipidcompound having the structure of general formula (I′):

-   -   wherein,    -   ring A is C₃₋₁₄ cycloalkyl, 3- to 14-membered heterocyclyl,        C₆₋₁₄ aryl or 5- to 14-membered heteroaryl; the ring A is        connected to the parent structure by a C atom on the ring; the        ring A is optionally further substituted;    -   G₁, G₂, G₃ or G₄ is each independently a bond, C₁₋₂₀ alkylene,        C₂₋₂₀ alkenylene or C₂₋₂₀ alkynylene;    -   G₈ or G₆ is each independently a bond or C₁₋₈ alkylene;    -   M₁ or M₂ is each independently biodegradable groups;    -   Q is a bond or biodegradable groups;    -   R₁ or R₂ is each independently C₄₋₂₈ alkyl, C₄₋₂₈ alkenyl or        C₄₋₂₈ alkynyl;    -   R′₃, R′₄, R′₅ or R′₆ is each independently C₁₋₈ alkyl;    -   each of the alkyl, alkenyl, alkynyl, alkylene, alkenylene,        alkynylene, cycloalkyl, heterocyclyl, aryl or heteroaryl is each        independently and optionally further substituted.

Further, the lipid compound has the structure of general formula (I′):

-   -   wherein,    -   ring A is C₃₋₁₄ cycloalkyl, 3- to 14-membered heterocyclyl,        C₆₋₁₄ aryl or 5- to 14-membered heteroaryl; the ring A is        connected to the parent structure by a C atom on the ring; the        ring A is optionally further substituted;    -   G₁, G₂, G₃ or G₄ is each independently a bond, C₁₋₂₀ alkylene,        C₂₋₂₀ alkenylene or C₂₋₂₀ alkynylene; the C₁₋₂₀ alkylene, C₂₋₂₀        alkenylene or C₂₋₂₀ alkynylene is optionally substituted with        one or more substituents selected from H, OH, alkyl,        hydroxyalkyl, alkoxy, amino, alkylamino, and dialkylamino;    -   G₈ or G₆ is each independently a bond or C₁₋₆ alkylene; the C₁₋₆        alkylene is optionally substituted with one or more substituents        selected from H, OH, alkyl, hydroxyalkyl, alkoxy, amino,        alkylamino, and dialkylamino;    -   M₁ or M₂ is each independently selected from —OC(O)—, —C(O)O—,        —SC(O)—, —C(O)S—, —O—, —OC(O)O—, —SC(O)O—, —OC(O)S—, —NR_(a)—,        —C(O)NR_(a)—, —NR_(a)C(O)—, —NR_(a)C(O)O—, —OC(O)NR_(a)—,        —NR_(a)C(O)S—, —SC(O)NR_(a)—, —NR_(a)C(O)NR_(a)—, —C(O)—,        —OC(S)—, —C(S)O—, —OC(S)NR_(a)—, —NR_(a)C(S)O—, —S—S— and        —S(O)_(m)—;    -   Q is selected from a bond, —OC(O)—, —C(O)O—, —SC(O)—, —C(O)S—,        —O—, —OC(O)O—, —SC(O)O—, —OC(O)S—, —NR_(b)—, —C(O)NR_(b)—,        —NR_(b)C(O)—, —NR_(b)C(O)O—, —OC(O)NR_(b)—, —NR_(b)C(O)S—,        —SC(O)NR_(b)—, —NR_(b)C(O)NR_(b)—, —C(O)—, —OC(S)—, —C(S)O—,        —OC(S)NR_(b)—, —NR_(a)C(S)O—, —S—S—, —S(O)_(n)—, phenylene and        pyridylidene; the phenylene or pyridylidene group is optionally        substituted with one or more substituents selected from H,        hydroxy, halogen, cyano, alkyl, hydroxyalkyl, haloalkyl and        alkoxy;    -   R₁ or R₂ is each independently C₄₋₂₈ alkyl, C₄₋₂₈ alkenyl or        C₄₋₂₈ alkynyl; the C₄₋₂₈ alkyl, C₄₋₂₈ alkenyl or C₄₋₂₈ alkynyl        is optionally substituted with one or more substituents selected        from H, OH, alkyl, hydroxyalkyl, alkoxy, amino, alkylamino, and        dialkylamino;    -   R′₃, R′₄, R′₅ or R′₆ is each independently C₁₋₈ alkyl;    -   each of R_(a) or R_(b) is each independently H, C₁₋₂₈ alkyl or        C₃₋₁₄ cycloalkyl; the C₁₋₂₈ alkyl or C₃₋₁₄ cycloalkyl is        optionally substituted with one or more substituents selected        from H, OH, alkyl, hydroxyalkyl, alkoxy, amino, alkylamino, and        dialkylamino;    -   m or n is each independently 0, 1 or 2.

Further, the G₁ and G₃ are both C₂-s alkylene, and G₂ and G₄ are both abond;

-   -   alternatively G₁ and G₃ are both C₅ alkylene, and G₂ and G₄ are        both a bond.

Further, the G₈ is a bond.

Further, the G₆ is a bond or C₁₋₆ alkylene.

Further, the M₁ or M₂ is each independently —C(O)O—, —OC(O)—, —C(O)S—,—SC(O)—, —NR_(a)C(O)— or —C(O)NR_(a)—, the R_(a) is H or C₄₋₂₄ alkyl;alternatively M₁ or M₂ is each independently —C(O)O— or —C(O)S—.

Further, the Q is a bond, —O—, —OC(O)—, —C(O)O—, —OC(O)O—, —OC(O)NH—,—NHC(O)—O—, —NHC(O)NH—, —OC(O)S—, or —SC(O)O—; alternatively Q is—C(O)O—.

Further, the ring A is 3- to 8-membered heterocyclyl, the ring A isoptionally substituted with one or more of R₇; alternatively the ring Ais

Further, the R₁ or R₂ is each independently C₄₋₂₈ alkyl, C₄₋₂₈ alkenylor C₄₋₂₈ alkynyl, the C₄₋₂₈ alkyl, C₄₋₂₈ alkenyl or C₄₋₂₈ alkynyl isoptionally substituted with one or more substituents H, hydroxyl orC₂₋₁₄ alkyl; alternatively R₁ or R₂ is each independently C₄₋₂₈ alkyl,C₄₋₂₈ alkenyl or C₄₋₂₈ alkynyl.

Further, the R′₃, R′₄, R′₅ or R′₆ is each independently C₁₋₃ alkyl;alternatively R′₃, R′₄, R′₅ or R′₆ are both methyl.

Further, each of the R′₇ is each independently H, halogen, cyano, OH,oxo, C₁₋₆ alkyl, C₁₋₆ alkoxy, —NH₂, —NHC₁₋₆ alkyl, or —N(C₁₋₆ alkyl)₂;the C₁₋₆ alkyl is optionally further substituted with a substituentselected from halogen, cyano, OH, oxo, —NH₂, —NHC₁₋₆ alkyl, and —N(C₁₋₆alkyl)₂; alternatively R′₇ is C₁₋₃ alkyl.

Further, the lipid compound is the compound of general formula (II′):

-   -   wherein the substituents are defined as described in general        formula (I′).

The present disclosure provides a lipid compound, a pharmaceuticallyacceptable salt or a stereoisomer thereof, wherein the lipid compound isselected from:

The present disclosure provides a composition, the composition comprisesa biologically active substance and lipid compounds of the presentdisclosure.

Further, the biologically active substance is DNA or RNA.

Further, the composition further comprises neutral lipids, structurelipids and polymeric lipids.

Further, the neutral lipids are DSPC, DMPC, DOPC, DPPC, POPC, DOPE,DMPE, POPE or DPPE.

Further, the structure lipids are selected from one of, or a combinationof cholesterol, sitosterol, coprosterol, fucosterol, brassicasterol,ergosterol, tomatine, ursolic acid, α-tocopherol, stigmasterol,avenasterol, ergocalciferol and campesterol.

Further, the polymeric lipids are selected from one of, or a combinationof DMPE-PEG1000, DPPE-PEG1000, DSPE-PEG1000, DOPE-PEG1000, DMG-PEG2000,Ceramide-PEG2000, DMPE-PEG2000, DPPE-PEG2000, DSPE-PEG2000,Azido-PEG2000, DSPE-PEG2000-Mannose, Ceramide-PEG5000, and DSPE-PEG5000.

The present disclosure provides a lipid nanoparticle comprising thelipid compound of the present disclosure or the composition of thepresent disclosure.

The present disclosure provides a pharmaceutical composition comprisingthe lipid compound of the present disclosure, the composition of thepresent disclosure or the lipid nanoparticle of the present disclosure,and pharmaceutically acceptable excipient(s).

The present disclosure provides the use of the lipid compound of thepresent disclosure, the composition of the present disclosure, the lipidnanoparticle of the present disclosure or the pharmaceutical compositionof the present disclosure in the manufacture of a medicament fortreating or preventing a disease.

The present disclosure provides a method for preparing the compound ofgeneral formula (II′), comprising:

-   -   reacting the compound of general formula (II′a) with the        compound of general formula (II′b), to give the compound of        general formula (II′);    -   wherein the substituents are defined as described in general        formula (I′).

The compounds of the present disclosure may include one or moreasymmetric centers, and thus may exist in a variety of stereoisomericforms, for example, enantiomers and/or diastereomers. For example, thecompounds of the present disclosure may be in the form of an individualenantiomer, diastereomer or geometric isomer (e.g., cis- andtrans-isomers), or may be in the form of a mixture of stereoisomers,including racemic mixture and a mixture enriched in one or morestereoisomers. The isomers can be separated from the mixture by themethods known to those skilled in the art, including chiral highpressure liquid chromatography (HPLC) and the formation andcrystallization of chiral salts; or alternative isomers can be preparedby asymmetric synthesis.

The compounds of the present disclosure may exist in tautomer forms. Thetautomer is a functional group isomer resulting from the rapid shift ofan atom between two positions in a molecule. The tautomer is a specialfunctional group isomer, wherein a pair of tautomers can convert betweeneach other, but usually exist in a relatively stable isomer as its mainform. The most important examples are the enol and keto tautomers.

The present disclosure also comprises compounds that are labeled withisotopes (isotope variants), which are equivalent to those described informula (IV), but one or more atoms are replaced by atoms having an atommass or mass number that are different from that of atoms that arecommon in nature. Examples of isotopes which may be introduced into thecompounds of the disclosure include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as ²H,³H, ¹³C, ¹¹C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²p ³⁵S, ¹⁸F and ³⁶C₁,respectively. Compounds of the present disclosure that comprise theabove isotopes and/or other isotopes of other atoms, prodrugs thereofand pharmaceutically acceptable salts of said compounds or prodrugs allare within the scope of the present disclosure. Certain isotope-labeledcompounds of the present disclosure, such as those incorporatingradioactive isotopes (e.g., ³H and ⁴C), can be used for the measurementof the distribution of drug and/or substrate in tissue. Tritium, whichis ³H and carbon-14, which is ¹⁴C isotope, are yet alternative, becausethey are easy to prepare and detect. Furthermore, replaced by heavierisotopes, such as deuterium, which is ²H, may provide therapeuticbenefits due to the higher metabolic stability, such as prolonging thehalf-life in vivo or decreasing the dosage requirements, and thus may bealternative in some cases. Isotope-labeled compounds of formula (I) ofthe present disclosure and prodrugs thereof can be prepared generally byusing readily available isotope-labeled reagents to replacenon-isotope-labeled reagents in the following schemes and/or theprocedures disclosed in the examples and preparation examples.

The present disclosure also provides a pharmaceutical formulationcomprising a therapeutically effective amount of a compound of formula(VI), or therapeutically acceptable salts thereof, and pharmaceuticallyacceptable carriers, diluents or excipients thereof. All of these formsbelong to the present disclosure.

Pharmaceutical Compositions and Kits

In another aspect, the present disclosure provides a pharmaceuticalcomposition comprising nanoparticle compositions of the presentdisclosure and pharmaceutically acceptable excipient(s), thenanoparticle composition comprises the compounds of the presentdisclosure.

A pharmaceutically acceptable excipient for use in the presentdisclosure refers to a non-toxic carrier, adjuvant or vehicle which doesnot destroy the pharmacological activity of the compound formulatedtogether. Pharmaceutically acceptable carriers, adjuvants, or vehiclesthat may be used in the compositions of the present disclosure include,but are not limited to, ion exchangers, alumina, aluminum stearate,lecithin, serum proteins (e.g., human serum albumin), buffer substances(such as phosphate), glycine, sorbic acid, potassium sorbate, a mixtureof partial glycerides of saturated plant fatty acids, water, salt orelectrolyte (such as protamine sulfate), disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salt, silica gel,magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based materials,polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, wax,polyethylene-polyoxypropylene block polymers, polyethylene glycol andlanolin.

The present disclosure also includes kits (e.g., pharmaceutical packs).Kits provided may include a nanoparticle composition of the presentdisclosure and other therapeutic, or diagnostic, or prophylactic agents,and a first and a second containers (e.g., vials, ampoules, bottles,syringes, and/or dispersible packages or other materials) containing thenanoparticle composition of the present disclosure or other therapeutic,or diagnostic, or prophylactic agents. In some embodiments, kitsprovided can also optionally include a third container containing apharmaceutically acceptable excipient for diluting or suspending thenanoparticle composition of the present disclosure and/or othertherapeutic, or diagnostic, or prophylactic agent. In some embodiments,the nanoparticle composition of the present disclosure provided in thefirst container and the other therapeutic, or diagnostic, orprophylactic agents provided in the second container is combined to forma unit dosage form.

Administration

The pharmaceutical composition provided by the present disclosure can beadministered by a variety of routes including, but not limited to, oraladministration, parenteral administration, inhalation administration,topical administration, rectal administration, nasal administration,oral administration, vaginal administration, administration by implantor other means of administration. For example, parenteral administrationas used herein includes subcutaneous administration, intradermaladministration, intravenous administration, intramuscularadministration, intra-articular administration, intraarterialadministration, intrasynovial administration, intrasternaladministration, intracerebroventricular administration, intralesionaladministration, and intracranial injection or infusion techniques.

Generally, the pharmaceutical compositions provided herein areadministered in an effective amount. The amount of the pharmaceuticalcomposition actually administered will typically be determined by aphysician, in the light of the relevant circumstances, including thecondition to be treated or prevented, the chosen route ofadministration, the actual pharmaceutical composition administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

When used to prevent the disorder of the present disclosure, thepharmaceutical compositions provided herein will be administered to asubject at risk for developing the condition, typically on the adviceand under the supervision of a physician, at the dosage levels describedabove. Subjects at risk for developing a particular condition generallyinclude those that have a family history of the condition, or those whohave been identified by genetic testing or screening to be particularlysusceptible to developing the condition.

The pharmaceutical compositions provided herein can also be administeredchronically (“chronic administration”). Chronic administration refers toadministration of a compound or pharmaceutical composition thereof overan extended period of time, e.g., for example, over 3 months, 6 months,1 year, 2 years, 3 years, 5 years, etc., or may be continuedindefinitely, for example, for the rest of the subject's life. Incertain embodiments, the chronic administration is intended to provide aconstant level of the compound in the blood, e.g., within thetherapeutic window over the extended period of time.

The pharmaceutical compositions of the present disclosure may be furtherdelivered using a variety of dosing methods. For example, in certainembodiments, the pharmaceutical composition may be given as a bolus,e.g., in order to raise the concentration of the compound in the bloodto an effective level. The placement of the bolus dose depends on thesystemic levels of the active ingredient desired throughout the body,e.g., an intramuscular or subcutaneous bolus dose allows a slow releaseof the active ingredient, while a bolus delivered directly to the veins(e.g., through an IV drip) allows a much faster delivery which quicklyraises the concentration of the active ingredient in the blood to aneffective level. In other embodiments, the pharmaceutical compositionmay be administered as a continuous infusion, e.g., by IV drip, toprovide maintenance of a steady-state concentration of the activeingredient in the subject's body. Furthermore, in still yet otherembodiments, the pharmaceutical composition may be administered as firstas a bolus dose, followed by continuous infusion.

The compositions for oral administration can take the form of bulkliquid solutions or suspensions, or bulk powders. More commonly,however, the compositions are presented in unit dosage forms tofacilitate accurate dosing. The term “unit dosage forms” refers tophysically discrete units suitable as unitary dosages for human subjectsand other mammals, each unit containing a predetermined quantity ofactive material calculated to produce the desired therapeutic effect, inassociation with a suitable pharmaceutical excipient.

Typical unit dosage forms include prefilled, premeasured ampules orsyringes of the liquid compositions or pills, tablets, capsules or thelike in the case of solid compositions. In such compositions, the activesubstance is usually a minor component (from about 0.1 to about 50% byweight or alternatively from about 1 to about 40% by weight) with theremainder being various vehicles or excipients and processing aidshelpful for forming the desired dosing form.

With oral dosing, one to five and especially two to four and typicallythree oral doses per day are representative regimens. Using these dosingpatterns, each dose provides from about 0.001 mg/kg to about 10 mg/kg ofthe therapeutic, or diagnostic, or prophylactic agents, with alternativedoses each providing from about 0.1 mg/kg to about 10 mg/kg, andespecially about 1 to about 5 mg/kg.

Transdermal doses are generally selected to provide similar or lowerblood levels than are achieved using injection doses, generally in anamount ranging from about 0.01 to about 20% by weight, alternativelyfrom about 0.1 to about 20% by weight, alternatively from about 0.1 toabout 10% by weight, and still alternatively from about 0.5 to about 15%by weight.

Injection dose levels range from about 0.1 mg/kg/hour to at least 10mg/kg/hour, all for from about 1 to about 120 hours and especially 24 to96 hours. A preloading bolus of from about 0.1 mg/kg to about 10 mg/kgor more may also be administered to achieve adequate steady statelevels. The maximum total dose is not expected to exceed about 2 g/dayfor a 40 to 80 kg human patient.

Liquid forms suitable for oral administration may include a suitableaqueous or nonaqueous vehicle with buffers, suspending and dispensingagents, colorants, flavors and the like. Solid forms may include, forexample, any of the following ingredients, or compounds of a similarnature: a binder such as microcrystalline cellulose, gum tragacanth orgelatin; an excipient such as starch or lactose, a disintegrating agentsuch as alginic acid, Primogel, or corn starch; a lubricant such asmagnesium stearate; a glidant such as colloidal silicon dioxide; asweetening agent such as sucrose or saccharin; or a flavoring agent suchas peppermint, methyl salicylate, or orange flavoring.

Injectable compositions are typically based upon injectable sterilesaline or phosphate-buffered saline or other injectable excipients knownin the art. As before, the active compound in such compositions istypically a minor component, often being from about 0.05 to 10% byweight with the remainder being the injectable excipient and the like.

Transdermal compositions are typically formulated as a topical ointmentor cream containing the active ingredient(s). When formulated as aointment, the active ingredients will typically be combined with eithera paraffinic or a water-miscible ointment base. Alternatively, theactive ingredients may be formulated in a cream with, for example anoil-in-water cream base. Such transdermal formulations are well-known inthe art and generally include additional ingredients to enhance thedermal penetration of stability of the active ingredients orFormulation. All such known transdermal formulations and ingredients areincluded within the scope provided herein.

The compounds provided herein can also be administered by a transdermaldevice. Accordingly, transdermal administration can be accomplishedusing a patch either of the reservoir or porous membrane type, or of asolid matrix variety.

The above-described components for orally administrable, injectable ortopically administrable compositions are merely representative. Othermaterials as well as processing techniques and the like are set forth inPart 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, MackPublishing Company, Easton, Pennsylvania, which is incorporated hereinby reference.

The nanoparticle compositions of the present disclosure can also beadministered in sustained release forms or from sustained release drugdelivery systems. A description of representative sustained releasematerials can be found in Remington's Pharmaceutical Sciences.

The present disclosure also relates to the pharmaceutically acceptableformulations of a compound of the present disclosure. In one embodiment,the formulation comprises water. In another embodiment, the formulationcomprises a cyclodextrin derivative. The most common cyclodextrins areα-, β- and γ-cyclodextrins consisting of 6, 7 and 8 α-1,4-linked glucoseunits, respectively, optionally comprising one or more substituents onthe linked sugar moieties, which include, but are not limited to,methylated, hydroxyalkylated, acylated, and sulfoalkylethersubstitution. In certain embodiments, the cyclodextrin is a sulfoalkylether β-cyclodextrin, e.g., for example, sulfobutyl etherβ-cyclodextrin, also known as Captisol. See, e.g., U.S. Pat. No.5,376,645. In certain embodiments, the formulation compriseshexapropyl-β-cyclodextrin (e.g., 10-50% in water).

EXAMPLE

In order to make the technical solutions of the present disclosureclearer and more explicit, the present disclosure is further elaboratedthrough the following examples. The following examples are used only toillustrate specific embodiments of the present disclosure so that aperson skilled in the art can understand the present disclosure, but arenot intended to limit the scope of protection of the present disclosure.The technical means or methods, etc. not specifically described in thespecific embodiments of the present disclosure are conventionaltechnical means or methods, etc. in the art. The materials, reagents,etc. used in examples are commercially available if not otherwisespecified.

TABLE 1 Abbreviation Full name THF Tetrahydrofuran DCM dichloromethaneMeOH methanol DMF N, N-Dimethylformamide DMSO Dimethyl sulfoxide DCE 1,2-Dichloroethane CDCl₃ Deuterated chloroform TBAI Tetrabutylammoniumiodide TSCH₂CN 4-Toluenesulfonylacetonitrile TMSOK Potassiumtrimethylsiloxide TBDMSCl tert-Butyldimethylsily1 chloride LDA Lithiumdiisopropylamide DMAP 4-Dimethylaminopyridine (COCl)₂ Oxalyl chlorideSOCl₂ Thionyl dichloride NaBH₄ Sodium borohydride NaH Sodium hydrideK₂CO₃ Potassium carbonate EDCI1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide DIPEAN,N-Diisopropylethylamine Et₃N Triethylamine AcOH Acetic acid NaBH₃CNSodium cyanoborohydride Imidazole Imidazole NMO 4-MethylmorpholineN-oxide BDMEP 2,6-di-tert-Butylpyridine

Example 1: Synthesis of Comound 1

A solution of compound 1-1 (100 g, 979 mmol) in tetrahydrofuran (800 mL)was cooled to −40° C. LDA (2 M, 490 mL) was added slowly dropwise to thesolution and the mixture was stirred for another 1 h after completion ofthe dropwise addition. A solution of 1-2 (315 g, 1.37 mol) intetrahydrofuran (100 mL) was added dropwise to the reaction system atthe same temperature and the reaction system was stirred overnight. Thereaction system was quenched with saturated aqueous ammonium chloride,and extracted with ethyl acetate. The organic phases were combined,dried over anhydrous sodium sulfate, and filtered. The filtrate wasconcentrated to dryness to give the crude product. The crude product waspurified by silica gel column to give compound 1-3 (115 g). ¹H NMR (400MHz, CDCl₃): δ ppm 1.06-1.11 (m, 6H), 1.13-1.22 (m, 2H), 1.29-1.39 (m,2H), 1.42-1.49 (m, 2H), 1.73-1.82 (m, 2H), 3.28-3.40 (m, 2H), 3.55-3.66(m, 3H).

A solution of compound 1-3 (100 g, 398 mmol), TsCH₂CN (38.9 g, 199 mmol)and TBAI (14.7 g, 39.8 mmol) in dimethyl sulfoxide (800 mL) was cooledto 0° C., and sodium hydride (20.7 g, 517 mmol) was added slowly inbatches. The mixture was reacted at room temperature overnight. Thereaction system was quenched with saturated aqueous sodium chloridesolution and extracted with ethyl acetate. The organic phases werecombined, dried over anhydrous sodium sulfate, and filtered. Thefiltrate was concentrated to dryness to give 115 g of crude compound1-4, which was used directly in the next reaction without isolation andpurification.

To a solution of compound 1-4 crude (110 g, 205 mmol) in dichloromethane(880 mL) was added 330 mL of concentrated hydrochloric acid, and themixture was reacted at room temperature for 2 h. The complete reactionof the substrate was monitored by TLC. The reaction system was quenchedwith saturated aqueous ammonium chloride solution and extracted withethyl acetate. The organic phases were combined, dried over anhydroussodium sulfate, and filtered. The filtrate was concentrated to drynessto give the crude product. The crude product was purified by silica gelcolumn to give compound 1-5 (30.0 g, 80.9 mmol, yield 39.4%).

TMSOK (11.0 g, 86.4 mmol) was added to a solution of compound 1-5 (8.0g, 21.6 mmol) in tetrahydrofuran (35.0 mL) at room temperature, and thereaction system was heated to 70° C. with stirring. The completeconsumption of reaction materials was monitored by TLC. The reactionsolution was cooled to room temperature, and the organic solvent wasremoved by rotary evaporation. The crude product was added to 20 mL ofwater and extracted with dichloromethane. The aqueous layer wascollected, and the solution was adjusted to a pH of <5 with 1 Mhydrochloric acid. The solution was extracted with dichloromethane. Theorganic phases were combined, dried over anhydrous sodium sulfate, andfiltered. The filtrate was collected and concentrated to give compound1-6 (7.0 g). ¹H NMR (400 MHz, CDCl₃): δ ppm 1.03 (s, 12H), 1.08-1.17 (m,8H), 1.34-1.45 (m, 8H), 2.21 (t, J=7.2 Hz, 4H).

Potassium carbonate (482 mg, 3.48 mmol) was added to a solution ofcompound 1-6 (294 mg, 0.87 mmol) and 1-7 (771 mg, 3.48 mmol) in DMF,then the reaction was warmed up to 60° C. for 6 h. The completedisappearance of reactant 1-6 was monitored. The mixture was cooled toroom temperature. The reaction system was quenched with saturatedaqueous sodium chloride solution and extracted with ethyl acetate. Theorganic phases were combined, dried over anhydrous sodium sulfate, andfiltered. The filtrate was concentrated to dryness to give the crudeproduct. The crude was purified by silica gel column to give compound1-8 (325 mg).

Compound 1-8 (325 mg) was dissolved in 4.0 mL of methanol and sodiumborohydride (30 mg, 0.84 mmol) was added to the reaction system. Themixture was reacted at room temperature. The complete disappearance ofthe reactants was monitored by TLC. The reaction system was quenchedwith saturated aqueous sodium chloride solution and extracted withdichloromethane. The organic phases were combined, dried over anhydroussodium sulfate, and filtered. The filtrate was concentrated to drynessto give crude compound 1-9 (260 mg), which was used directly in the nextreaction without purification.

Crude compound 1-9 (260 mg, 0.42 mmol), 1-10 (73.1 mg, 0.63 mmol), EDCI(238 mg, 1.26 mmol), triethylamine (0.17 mL, 1.26 mmol) and DMAP (51 mg,0.42 mmol) were dissolved in 5.0 mL of dichloromethane, and the reactionsolution was stirred to react at room temperature for 12 h. The reactionsolution was quenched with saturated aqueous sodium chloride andextracted with dichloromethane. The organic phases were combined, driedover anhydrous sodium sulfate, and filtered. The organic phase wascollected and the organic solvent was removed using a rotary-evaporatorto give the crude product, which was purified by preparative highperformance liquid chromatography to give compound 1 (130 mg).

¹H NMR (400 MHz, CDCl₃): δ ppm 0.89 (t, J=7.2 Hz, 6H), 1.15 (s, 12H),1.27 (m, 40H), 1.49 (m, 8H), 1.61 (m, 4H), 2.26 (s, 6H), 2.44-2.52 (t,J=7.2 Hz, 2H), 2.63 (t, J=7.2 Hz, 2H), 4.04 (t, J=6.8 Hz, 4H), 4.86 (m,1H); ESI-MS m/z: 724.7 [M+H]⁺.

Example 2: Synthesis of Compound 2

Referring to the method of Example 1, compound 2 was prepared as an oilyproduct: 25.7 mg.

¹H NMR (400 MHz, CDCl₃): δ ppm 0.89 (t, J=6.8 Hz, 6H), 1.15 (s, 12H),1.29 (m, 32H), 1.49 (m, 8H), 1.60 (m, 4H), 2.24 (s, 6H), 2.46 (t, J=7.2Hz, 2H), 2.61 (t, J=7.2 Hz, 2H), 4.04 (t, J=6.8 Hz, 4H), 4.86 (m, 1H);ESI-MS m/z: 668.6 [M+H]⁺.

Example 3: Synthesis of Compound 3

Referring to the method of Example 1, compound 3 was prepared as an oilyproduct: 31.2 mg.

¹H NMR (400 MHz, CDCl₃): δ ppm 0.89 (t, J=6.8 Hz, 6H), 1.16 (s, 12H),1.28 (m, 36H), 1.49 (m, 8H), 1.62 (m, 4H), 2.25 (s, 6H), 2.47 (t, J=7.2Hz, 2H), 2.62 (t, J=7.2 Hz, 2H), 4.05 (t, J=6.8 Hz, 4H), 4.88 (m, 1H);ESI-MS m/z: 696.6 [M+H]⁺.

Example 4: Synthesis of Compound 4

Referring to the method of Example 1, compound 4 was prepared as an oilyproduct: 32 mg.

¹H NMR (400 MHz, CDCl₃): δ ppm 0.89 (t, J=6.8 Hz, 6H), 1.16 (s, 12H),1.28 (m, 44H), 1.49 (m, 8H), 1.52 (m, 4H), 2.51 (s, 6H), 2.53 (t, J=7.2Hz, 2H), 3.12 (t, J=7.2 Hz, 2H), 3.91 (t, J=6.8 Hz, 4H), 4.82 (m, 1H);ESI-MS m/z: 752.7 [M+H]⁺.

Example 5: Synthesis of Compound 5

Referring to the method of Example 1, compound 5 was prepared as an oilyproduct: 31.4 mg.

¹H NMR (400 MHz, CDCl₃): δ ppm 0.88 (t, J=6.8 Hz, 6H), 1.15 (s, 12H),1.25 (m, 48H), 1.49 (m, 8H), 1.52 (m, 4H), 2.46 (s, 6H), 2.63 (m, 2H),2.86 (m, 2H), 4.03 (t, J=6.8 Hz, 4H), 4.84 (m, 1H); ESI-MS m/z: 780.7[M+H]⁺.

Example 6: Synthesis of Compound 6

Referring to the method of Example 1, compound 6 was prepared as an oilyproduct: 30.7 mg.

¹H NMR (400 MHz, CDCl₃): δ ppm 0.83 (t, J=6.8 Hz, 18H), 1.00-1.28 (m,34H), 1.31-1.62 (m, 18H), 2.21 (s, 6H), 2.36-2.46 (m, 2H), 2.51-2.62 (m,2H), 4.02 (t, J=6.8 Hz, 4H), 4.71-4.85 (m, 1H); ESI-MS m/z: 724.6[M+H]⁺.

Example 7: Synthesis of Compound 7

Compound 1-6 (548 mg, 1.5 mmol) was dissolved in 5.0 mL ofdichloromethane, and the reaction system was cooled to 0° C. in an icebath. DMF (12 μL, 0.15 mmol) was added and oxalyl chloride (0.47 mL, 6.0mmol) was added dropwise to the reaction solution. The ice bath wasremoved and the mixture was stirred for 1 h at room temperature. Thesolvent was removed using a rotary-evaporator to give acyl chloridecrude product (458 mg) as an oil, which was used directly in the nextreaction step.

The above obtained acyl chloride crude product (458 mg) was dissolved in3.0 mL of 1,2-dichloroethane, and then compound 7-1 (429 mg, 3.0 mmol)was added to the reaction solution. The mixture was stirred at roomtemperature until the substrate was reacted completely. The solvent wasremoved using a rotary-evaporator to give the crude product, which waspurified by silica gel column to give compound 7-2 (540 mg).

Then referring to the method of Example 1, compound 7 was prepared as anoily product: 33.2 mg.

¹H NMR (400 MHz, CDCl₃): δ ppm 0.89 (t, J=6.8 Hz, 6H), 1.23 (s, 12H),1.29-1.51 (m, 32H), 1.95 (m, 8H), 2.18 (s, 6H), 2.41 (m, 2H), 2.53 (m,2H), 3.91 (t, J=6.8 Hz, 4H), 4.78 (m, 1H), 5.25 (m, 4H); ESI-MS m/z:692.6 [M+H]⁺.

Example 8: Synthesis of Compound 8

Compound 1-6 (548 mg, 1.5 mmol) was dissolved in 5.0 mL ofdichloromethane, and the reaction system was cooled in an ice bath. DMF(12 μL, 0.15 mmol) was added and oxalyl chloride (0.47 mL, 6.0 mmol) wasadded dropwise to the reaction solution. The ice bath was removed andthe mixture was stirred for 1 h at room temperature. The solvent wasremoved using a rotary-evaporator to give acyl chloride crude product(458 mg) as an oil, which was used directly in the next reaction step.

The above obtained 458 mg of acyl chloride crude product was dissolvedin 3.0 mL of 1,2-dichloroethane, and then compound 8-1 (472 mg, 3.0mmol) was added to the reaction solution. The mixture was stirred atroom temperature until the substrate was reacted completely. The solventwas removed using a rotary-evaporator to give crude product, which waspurified by silica gel column to give compound 8-2 (518 mg).

518 mg of compound 8-2 was dissolved in 5.0 mL of methanol, and sodiumborohydride (48 mg, 1.25 mmol) was added to the reaction system. Themixture was reacted at room temperature. The complete disappearance ofthe reactants was monitored by TLC. The reaction system was quenchedwith saturated aqueous sodium chloride solution and extracted withdichloromethane. The organic phases were combined, dried over anhydroussodium sulfate, and filtered. The filtrate was concentrated to drynessto give 473 mg of crude compound 8-3, which was used directly in thenext reaction without purification.

Crude compound 8-3 (270 mg, 0.43 mmol), 1-10 (76.1 mg, 0.65 mmol), EDCI(248 mg, 1.3 mmol), triethylamine (0.18 mL, 1.3 mmol) and DMAP (53 mg,0.43 mmol) were dissolved in 5.0 mL of dichloromethane, and the reactionsolution was stirred to react at room temperature for 12 h. The reactionsystem was quenched with saturated aqueous sodium chloride and extractedwith dichloromethane. The organic phases were combined, dried overanhydrous sodium sulfate, and filtered. The organic phase was collectedand the organic solvent was removed using a rotary-evaporator to givethe crude product, which was purified by preparative high performanceliquid chromatography to give compound 8 (39 mg).

¹H NMR (400 MHz, CDCl₃): δ ppm 0.89 (t, J=6.8 Hz, 6H), 1.14 (s, 12H),1.15-1.31 (m, 40H), 1.40-1.52 (m, 12H), 2.25 (s, 6H), 2.45 (m, 2H), 2.60(m, 2H), 3.15 (t, J=6.8 Hz, 4H), 4.77-4.89 (m, 1H), 5.51-5.67 (m, 2H);ESI-MS m/z: 722.7 [M+H]⁺.

Example 9: Synthesis of Compound 9

Referring to the method of Example 8, compound 9 (73 mg) was prepared.

¹H NMR (400 MHz, CDCl₃): δ ppm 0.89 (t, J=6.8 Hz, 6H), 1.15 (s, 12H),1.27-1.49 (m, 48H), 2.25 (s, 6H), 2.46 (t, J=7.2 Hz, 2H), 2.62 (t, J=7.2Hz, 2H), 3.24 (m, 4H), 4.85 (m, 1H), 5.58 (m, 2H); ESI-MS m/z: 694.6[M+H]⁺.

Example 10: Synthesis of Compound 10

Referring to the method of Example 8, compound 10 (31.2 mg) wasprepared.

¹H NMR (400 MHz, CDCl₃): δ ppm 0.79 (t, J=7.2 Hz, 6H), 1.07 (s, 12H),1.27-1.49 (m, 48H), 1.41 (m, 12H), 2.18 (s, 6H), 2.41 (t, J=7.2 Hz, 2H),2.55 (t, J=7.2 Hz, 2H), 3.16 (m, 4H), 4.78 (m, 1H), 5.51 (m, 2H); ESI-MSm/z: 778.8 [M+H]⁺.

Example 11: Synthesis of Compound 11

Referring to the method of Example 8, compound 11 (48.1 mg) wasprepared.

¹H NMR (400 MHz, CDCl₃): δ ppm 0.78 (t, J=7.2 Hz, 12H), 1.07 (s, 12H),1.14-1.19 (m, 60H), 1.40 (m, 16H), 2.18 (s, 6H), 2.36-2.47 (m, 2H),2.49-2.68 (m, 2H), 3.76-3.88 (m, 2H), 4.74-4.83 (m, 1H), 5.10-5.19 (m,2H); ESI-MS m/z: 918.9 [M+H]⁺.

Example 12: Synthesis of Compound 12

Referring to the method of Example 8, compound 12 (52 mg) was prepared.

¹H NMR (400 MHz, CDCl₃): δ ppm 0.82 (t, J=6.8 Hz, 12H), 1.15-1.32 (m,72H), 1.54 (m, 16H), 2.31 (s, 6H), 2.51 (t, J=7.2 Hz, 2H), 2.60 (t,J=7.2 Hz, 2H), 3.14-3.33 (m, 8H), 4.75-4.83 (m, 1H); ESI-MS m/z: 946.9[M+H]⁺.

Example 13: Synthesis of Compound 13

Referring to the method of Example 8, compound 13 (32 mg) was prepared.

¹H NMR (400 MHz, CDCl₃): δ ppm 0.81 (t, J=7.2 Hz, 6H), 1.19 (m, 52H),1.41 (m, 12H), 2.26 (s, 6H), 3.05 (s, 2H), 3.16 (m, 4H), 4.83 (m, 1H),5.51 (m, 2H); ESI-MS m/z: 708.7 [M+H]⁺.

Example 14: Synthesis of Compound 14

Referring to the method of Example 8, compound 14 (18 mg) was prepared.

¹H NMR (400 MHz, CDCl₃): δ ppm 0.81 (t, J=7.2 Hz, 6H), 1.07 (s, 12H),1.08-1.31 (m, 44H), 1.35-1.47 (m, 8H), 1.71-1.84 (m, 2H), 2.09-2.38 (m,10H), 3.12-3.27 (m, 4H), 4.70-4.82 (m, 1H), 5.49-5.63 (m, 2H); ESI-MSm/z: 736.7 [M+H]⁺.

Example 15: Synthesis of Compound 15

A solution of compound 15-1 (400 mg, 1.4 mmol) in dichloromethane (3.0mL) was cooled to 0° C., then a solution of SOCl₂ (0.12 mL, 1.68 mmol)in dichloromethane (2.0 mL) was added dropwise. After the dropwiseaddition was completed, the mixture was stirred at 0° C. for another 1h. After the reaction was completed, the reaction was quenched by addingsaturated sodium bicarbonate solution to the reaction system, and thereaction system was extracted with dichloromethane. The organic phaseswere combined and the organic solvent was removed to give crude compound15-2, which was used directly in the next reaction without purification.

Compound 1-6 (223, 0.65 mmol), 15-2 (496 mg, 1.63 mmol) and potassiumcarbonate (361 mg, 2.6 mmol) were dissolved in 5.0 mL of DMF and thereaction solution was heated to 70° C. to react for 6 hours. Thereaction solution was cooled to room temperature, then the reaction wasquenched by adding saturated sodium chloride solution to the reactionsystem, and the reaction system was extracted with dichloromethane. Theorganic phases were combined and the organic solvent was removed to givethe crude product. The crude was purified by silica gel column to givecompound 15-3.

Then referring to the method of Example 1, compound 15 (40 mg) wasprepared.

¹H NMR (400 MHz, CDCl₃): δ ppm 0.89 (t, J=7.2 Hz, 12H), 1.08 (s, 12H),1.12-1.35 (m, 46H), 1.38-1.58 (m, 22H), 2.35 (s, 6H), 2.41-2.52 (m,10H), 2.57-2.65 (m, 2H), 2.62 (m, 4H), 4.10 (t, J=6.4 Hz, 4H), 4.86 (m,1H); ESI-MS m/z: 978.9 [M+H]⁺.

Example 16: Synthesis of Compound 16

DMF (11 μL, 0.14 mmol) was added to a solution of compound 1-6 (460 mg,1.34 mmol) in dichloromethane (5.0 mL) under ice bath conditions, andoxalyl chloride (0.47 mL, 5.37 mmol) was then added dropwise to thereaction solution. The ice bath was removed, and the mixture was stirredfor 1 h at room temperature. The solvent was removed using arotary-evaporator to give 255 mg of acyl chloride crude product as anoil, which was used directly in the next reaction step.

The above obtained acyl chloride crude product (255 mg, 0.67 mmol) wasdissolved in 3.0 mL of 1,2-dichloroethane, and then compound 16-1 (384mg, 1.68 mmol) was added to the reaction solution. The mixture wasstirred at room temperature until the substrate was reacted completely.The solvent was removed using a rotary-evaporator to give the crudeproduct, which was purified by silica gel column to give 300 mg ofcompound 16-2.

¹H NMR (400 MHz, CDCl₃): δ ppm 0.78-0.83 (m, 12H), 1.07 (s, 12H),1.13-1.22 (m, 48H), 1.49 (br s, 16H), 2.29 (t, J=7.50 Hz, 4H), 4.76 (m,2H).

Compound 16-2 (300 mg, 0.39 mmol) was dissolved in 4.0 mL of methanol.Then NaBH₄ (45 mg, 1.17 mmol) was slowly added to the reaction solutionand the mixture was stirred at room temperature for 2 h. The reactionsolution was quenched with saturated ammonium chloride solution,extracted with ethyl acetate. The organic phases were combined and theorganic solvent was removed to give 300 mg of crude compound 16-3, whichwas used directly in the next reaction without purification.

Crude compound 16-3 (300 mg, 0.39 mmol) was dissolved in 2.0 mL DMF, andthen 1-10 (69 mg, 0.59 mmol), EDCI (225 mg, 1.17 mmol), triethylamine(119 mg, 1.17 mmol) and DMAP (48 mg, 0.39 mmol) were added. The mixturewas stirred at room temperature until the reactants was reactedcompletely. The reaction solution was quenched with saturated sodiumchloride solution and extracted with ethyl acetate. The organic phaseswere combined, dried over anhydrous sodium sulfate, and filtered. Thefiltrate was concentrated to dryness to give the crude product. Thecrude product was purified by preparative high performance liquidchromatography to give compound 16 (32.5 mg).

¹H NMR (400 MHz, CDCl₃): δ ppm 0.79 (t, J=7.2 Hz, 12H), 1.07 (s, 12H),1.19 (m, 52H), 1.40-1.46 (m, 16H), 2.15 (s, 6H), 2.34-2.58 (m, 4H),4.74-4.81 (m, 3H); ESI-MS m/z: 864.8 [M+H]⁺.

Example 17: Synthesis of Compound 17

Referring to the method of Example 1, compound 17 was prepared as anoily product: 41.3 mg.

¹H NMR (400 MHz, CDCl₃): δ ppm 0.82 (t, J=7.2 Hz, 6H), 1.08 (s, 12H),1.14-1.20 (m, 36H), 1.40-1.64 (m, 16H), 2.32 (s, 6H), 3.08-3.21 (m, 2H),3.97 (t, J=7.2 Hz, 4H), 4.83-4.92 (m, 1H); ESI-MS m/z: 710.6 [M+H]⁺.

Example 18: Synthesis of Compound 18

Referring to the method of Example 1, compound 18 was prepared as anoily product: 35.4 mg.

¹H NMR (400 MHz, CDCl₃): δ ppm 0.79 (t, J=7.2 Hz, 6H), 1.08 (s, 12H),1.13-1.25 (m, 36H), 1.28-1.47 (m, 10H), 1.47-1.62 (m, 6H), 1.68-1.79 (m,2H), 2.15 (s, 6H), 2.21-2.31 (m, 4H), 3.97 (t, J=7.2 Hz, 4H), 4.73-4.82(m, 1H); ESI-MS m/z: 738.7 [M+H]⁺.

Example 19: Synthesis of Compound 19

Referring to the method of Example 1, compound 19 was prepared as anoily product: 33.1 mg.

¹H NMR (400 MHz, CDCl₃): δ ppm 0.89 (t, J=7.2 Hz, 6H), 1.15 (s, 12H),1.29 (m, 30H), 1.50 (m, 8H), 1.60 (m, 6H), 1.64 (m, 2H), 2.23 (s, 6H),2.33 (m, 4H), 4.05 (t, J=6.8 Hz, 4H), 4.86 (m, 1H); ESI-MS m/z: 682.6[M+H]⁺.

Example 20: Synthesis of Compound 20

Referring to the method of Example 1, compound 20 was prepared as anoily product: 302 mg.

¹H NMR (400 MHz, CDCl₃): δ ppm 0.89 (t, J=7.2 Hz, 6H), 1.15 (s, 12H),1.27 (m, 34H), 1.47 (m, 8H), 1.51 (m, 6H), 1.79 (m, 2H), 2.23 (s, 6H),2.33 (m, 4H), 4.04 (t, J=6.8 Hz, 4H), 4.85 (m, 1H); ESI-MS m/z: 710.7[M+H]⁺.

Example 21: Synthesis of Compound 21

Referring to the method of Example 1, compound 21 was prepared as anoily product: 31.2 mg.

¹H NMR (400 MHz, CDCl₃): δ ppm 0.79 (t, J=7.2 Hz, 6H), 1.08 (s, 12H),1.25 (m, 44H), 1.39 (m, 8H), 1.51 (m, 4H), 1.82 (m, 2H), 2.25 (t, J=7.2Hz, 2H), 2.32 (s, 6H), 2.41 (m, 2H), 3.96 (t, J=6.8 Hz, 4H), 4.75 (m,1H); ESI-MS m/z: 766.7 [M+H]⁺.

Example 22: Synthesis of Compound 22

Referring to the method of Example 1, compound 22 was prepared as anoily product: 31.8 mg.

¹H NMR (400 MHz, CDCl₃): δ ppm 0.79 (t, J=7.2 Hz, 6H), 1.07 (s, 12H),1.28 (m, 48H), 1.40 (m, 8H), 1.53 (m, 4H), 1.84 (m, 2H), 2.26 (t, J=7.2Hz, 2H), 2.35 (s, 6H), 2.48 (m, 2H), 3.98 (t, J=6.8 Hz, 4H), 4.75 (m,1H); ESI-MS m/z: 794.7 [M+H]⁺.

Example 23: Synthesis of Compound 23

Referring to the method of Example 7, compound 23 was prepared as anoily product: 31.0 mg.

¹H NMR (400 MHz, CDCl₃): δ ppm 0.87 (t, J=7.2 Hz, 6H), 1.16 (s, 12H),1.20-1.39 (m, 28H), 1.45-1.54 (m, 12H), 1.74-1.82 (m, 2H), 2.12-2.35 (m,14), 4.63 (t, J=2.4 Hz, 4H), 4.79-4.88 (m, 1H); ESI-MS m/z: 730.6[M+H]⁺.

Example 24: Synthesis of Compound 24

Referring to the method of Example 7, compound 24 was prepared as anoily product: 31.0 mg.

¹H NMR (400 MHz, CDCl₃): δ ppm 0.88 (t, J=7.2 Hz, 6H), 1.15 (s, 12H),1.20-1.38 (m, 24H), 1.43-1.52 (m, 12H), 1.76-1.84 (m, 2H), 2.09-2.14 (m,4H), 2.23 (s, 6H), 2.28-2.36 (m, 4H), 2.43-2.49 (m, 4H), 4.10 (t, J=7.2Hz, 4H), 4.80-4.88 (m, 1H); ESI-MS m/z: 730.6 [M+H]⁺.

Example 25: Synthesis of Compound 25

Referring to the method of Example 7, compound 25 was prepared as anoily product: 32.1 mg.

¹H NMR (400 MHz, CDCl₃): δ ppm 0.84 (t, J=7.2 Hz, 6H), 1.08 (s, 12H),1.02-1.21 (m, 12H), 1.38-1.47 (m, 22H), 1.59-1.78 (m, 6H), 2.02-2.17 (m,14H), 2.19-2.30 (m, 4H), 4.01 (t, J=6.8 Hz, 4H), 4.71-4.83 (m, 1H);ESI-MS m/z: 730.6 [M+H]⁺.

Example 26: Synthesis of Compound 26

Compound 23 (300 mg, 0.41 mmol) and quinoline (106 mg, 0.82 mmol) weredissolved in 3.0 mL of ethyl acetate, and the air in the reaction systemwas replaced with nitrogen for 2-3 min at room temperature, then lindlarcatalyst (16.9 mg) was added. Hydrogen gas was introduced to thereaction solution and the air was replaced with hydrogen for 2˜3 min.The reaction system was kept under hydrogen atmosphere (15 psi) at roomtemperature for 30 min. The complete disappearance of the reactants wasmonitored by LC-MS. The reaction solution was filtered, and the filtercake was rinsed with ethyl acetate 3-4 times. The combined ethyl acetatewas collected and the organic solvent was removed using arotary-evaporator to give the crude product, which was purified bypreparative high performance liquid chromatography to give compound 26(31.3 mg).

¹H NMR (400 MHz, CDCl₃): δ ppm 0.81 (t, J=7.2 Hz, 6H), 1.08 (s, 12H),1.15-1.28 (m, 32H), 1.38-1.44 (m, 8H), 1.70-1.79 (m, 2H), 2.01 (m, 4H),2.15 (s, 6H), 2.16-2.28 (m, 4H), 4.54 (d, J=12.0 Hz, 4H), 4.75 (m, 1H),5.39-5.59 (m, 4H); ESI-MS m/z: 734.6 [M+H]⁺.

Example 27: Synthesis of Compound 27

Referring to the method of Example 26, compound 27 was prepared as anoily product: 35.0 mg.

¹H NMR (400 MHz, CDCl₃): δ ppm 0.82 (m, 6H), 1.08 (s, 12H), 1.14-1.31(m, 28H), 1.37-1.45 (m, 8H), 1.70-1.79 (m, 2H), 1.96 (m, 4H), 2.06-2.36(m, 14H), 3.98 (t, J=7.2 Hz, 4H), 4.74-4.82 (m, 1H), 5.22-5.31 (m, 2H),5.37-5.48 (m, 2H); ESI-MS m/z: 734.7 [M+H]⁺.

Example 28: Synthesis of Compound 28

Referring to the method of Example 26, compound 28 was prepared as anoily product: 31.8 mg.

¹H NMR (400 MHz, CDCl₃): δ ppm 0.92 (t, J=6.8 Hz, 6H), 1.18 (s, 12H),1.21-1.39 (m, 22H), 1.40-1.59 (m, 12H), 1.60-1.72 (m, 4H), 1.89-2.01 (m,2H), 2.02-2.15 (m, 8H), 2.34-2.69 (m, 8H), 4.08 (t, J=6.4 Hz, 4H),4.82-4.92 (m, 1H), 5.30-5.48 (m, 4H); ESI-MS m/z: 734.6 [M+H]⁺.

Example 30: Synthesis of Compound 30

Referring to the method of Example 1, compound 30 was prepared as anoily product: 33.0 mg.

¹H NMR (400 MHz, CDCl₃): δ ppm 0.92 (t, J=6.8 Hz, 6H), 1.18 (s, 12H),1.19-1.37 (m, 36H), 1.45-1.57 (m, 8H), 1.58-1.74 (m, 8H), 2.27-2.50 (m,8H), 4.07 (t, J=6.8 Hz, 4H), 4.83-4.90 (m, 1H); ESI-MS m/z: 710.6[M+H]⁺.

Example 32: Synthesis of Compound 32

Referring to the method of Example 1, compound 32 was prepared as anoily product: 31.1 mg.

¹H NMR (400 MHz, CDCl₃): δ ppm 0.80 (t, J=6.8 Hz, 6H), 1.08 (s, 12H),1.20-1.27 (m, 34H), 1.34-1.47 (m, 12H), 1.48-1.62 (m, 8H), 2.15 (s, 6H),2.19-2.24 (m, 4H), 3.97 (t, J=6.8 Hz, 4H), 4.74-4.80 (m, 1H); ESI-MSm/z: 738.6 [M+H]⁺.

Example 33: Synthesis of Compound 33

Compound 1-6 (448 mg, 1.3 mmol) was dissolved in 5.0 mL ofdichloromethane, and the reaction system was cooled to 0° C. in an icebath. DMF (10 μL, 0.13 mmol) was added, and oxalyl chloride (0.44 mL,5.2 mmol) was then added dropwise to the reaction solution. The ice bathwas removed after the dropwise addition was completed and the mixturewas stirred for 1 h at room temperature. The solvent was removed using arotary-evaporator to give acyl chloride crude product (330 mg) as anoil, which was used directly in the next reaction step.

1-Decanethiol 33-1 (455 mg, 2.61 mmol) was added to a solution of crudeacyl chloride (330 mg, 0.87 mmol) in DCE (3.0 mL), and the reaction washeated to 70° C. to react overnight. The reaction solution was cooled toroom temperature and the solvent was removed using a rotary-evaporatorto give the crude product, which was purified by silica gel column togive compound 33-2 (400 mg). ¹H NMR (400 MHz, CDCl₃): δ ppm 0.84-0.87(m, 6H), 1.14-1.18 (m, 12H), 1.20-1.28 (m, 36H), 1.48-1.55 (m, 12H),2.33 (t, J=7.2 Hz, 4H), 2.79 (t, J=7.2 Hz, 4H).

Compound 33-2 (300 mg, 0.46 mmol) was dissolved in 3.0 mL of methanoland NaBH₄ (52.5 mg, 1.38 mmol) was added in batches. The reactionsolution was stirred under nitrogen atmosphere at room temperature for 2h. The complete disappearance of the reaction material was monitored byTLC. The reaction solution was quenched by adding saturated ammoniumchloride solution, and extracted with ethyl acetate. The organic phaseswere combined, dried over anhydrous sodium sulfate, and filtered. Thefiltrate was collected and concentrated to give 300 mg of crude compound33-3, which was directly used in the next reaction step without furtherpurification.

Crude compound 33-3 (150 mg, 0.23 mmol) was dissolved in 3.0 mL ofdichloromethane, and 1-10 (80.2 mg, 0.69 mmol), EDCI (131 mg, 0.69mmol), triethylamine (0.1 mL, 0.69 mmol) and DMAP (28 mg, 0.23 mmol)were added to the reaction system. The reaction solution was stirred atroom temperature for 12 h. The reaction solution was then quenched byadding saturated ammonium chloride solution, and extracted withdichloromethane. The organic phases were combined, dried over anhydroussodium sulfate, and filtered. The filtrate was collected andconcentrated to give the crude product, which was passed throughpreparative high performance liquid chromatography to give compound 33(28.6 mg).

¹H NMR (400 MHz, CDCl₃): δ ppm 0.81 (t, J=7.2 Hz, 6H), 1.15 (s, 12H),1.31 (m, 40H), 1.48 (m, 12H), 2.23 (s, 6H), 2.42 (m, 4H), 2.80 (t, J=7.2Hz, 4H), 4.82 (m, 1H); ESI-MS m/z: 756.6 [M+H]⁺.

Example 34: Synthesis of Compound 34

Referring to the method of Example 33, compound 34 was prepared as anoily product: 105.2 mg.

¹H NMR (400 MHz, CDCl₃): δ ppm 0.85 (t, J=7.2 Hz, 6H), 1.15 (s, 12H),1.6-1.32 (m, 40H), 1.37-1.53 (m, 14H), 1.75 (m, 2H), 2.24-2.34 (m, 8H),2.80 (t, J=7.2 Hz, 4H), 4.72-4.82 (m, 1H); ESI-MS m/z: 770.6 [M+H]⁺.

Example 36: Synthesis of Compound 36

Referring to the method of Example 33, compound 36 was prepared as anoily product: 33.4 mg.

¹H NMR (400 MHz, CDCl₃): δ ppm 0.86 (t, J=6.8 Hz, 6H), 1.16 (s, 12H),1.18-1.38 (m, 40H), 1.41-1.59 (m, 16H), 1.61-1.67 (m, 2H), 2.19-2.33 (m,10H), 2.82 (t, J=7.2 Hz, 4H), 4.83 (m, H); ESI-MS m/z: 798.6 [M+H]⁺.

Example 37: Synthesis of Compound 37

Referring to the method of Example 33, compound 37 was prepared as anoily product: 33.2 mg.

¹H NMR (400 MHz, CDCl₃): δ ppm 0.87 (t, J=6.8 Hz, 6H), 1.20 (s, 12H),1.19-1.37 (m, 36H), 1.39-1.56 (m, 12H), 1.75-1.84 (m, 2H), 2.24 (s, 6H),2.28-2.34 (m, 4H), 2.81 (t, J=7.2 Hz, 4H), 4.79-4.87 (m, 1H); ESI-MSm/z: 742.6 [M+H]⁺.

Example 39: Synthesis of Compound 39

Referring to the method of Example 33, compound 39 was prepared as anoily product: 30.7 mg.

¹H NMR (400 MHz, CDCl₃): δ ppm 0.91 (t, J=7.2 Hz, 6H), 1.22 (s, 12H),1.17-1.38 (m, 32H), 1.47-1.58 (m, 12H), 1.78-1.87 (m, 2H), 2.28 (s, 6H),2.34-2.37 (m, 4H), 2.85 (t, J=7.2 Hz, 4H), 4.81-4.90 (m, 1H); ESI-MSm/z: 714.6 [M+H]⁺.

Example 40: Synthesis of Compound 40

Potassium carbonate (1.55 g, 11.2 mmol, 4.0 eq.) was added to a solutionof compound 1-6 (959 mg, 2.8 mmol, 1.0 eq.) and 3-1 (638 mg, 3.08 mmol,1.1 eq.) in DMF. Then the reaction was warmed up to 60° C. for 4 h. Thereaction was cooled to room temperature. The reaction system wasquenched with saturated aqueous sodium chloride solution and extractedwith ethyl acetate. The organic phases were combined, dried overanhydrous sodium sulfate, and filtered. The filtrate was concentrated todryness to give the crude product, which was purified by silica gelcolumn to give compound 40-1 (682 mg).

Compound 40-1 (324 mg, 0.69 mmol, 1.0 eq.) was dissolved in 5.0 mL ofdichloromethane, and the reaction system was cooled to 0° C. in an icebath. 2 drops of DMF were added and oxalyl chloride (0.24 mL, 2.8 mmol,4.0 eq.) was then added dropwise to the reaction solution. The ice bathwas removed after the dropwise addition was completed and the mixturewas stirred for 1 h at room temperature. The solvent was removed using arotary-evaporator to give acyl chloride crude product (309 mg) as anoil, which was used directly in the next reaction step.

1-Decanethiol 33-1 (331 mg, 1.9 mmol, 3.0 eq) was added to a solution ofcrude acyl chloride (309 mg) in DCE (3.0 mL), and the reaction washeated to 70° C. to react overnight. The reaction solution was cooled toroom temperature and the solvent was removed using a rotary-evaporatorto give the crude product, which was purified by silica gel column togive compound 40-2 (274 mg).

Then referring to the method of Example 1, compound 40 was prepared asan oily product: 34.2 mg.

¹H NMR (400 MHz, CDCl₃): δ ppm 0.81 (t, J=7.2 Hz, 6H), 1.05 (s, 6H),1.12 (s, 6H), 1.08-1.28 (m, 36H), 1.37-1.57 (m, 14H), 1.71-1.76 (m, 2H),2.22 (s, 6H), 2.25-2.31 (m, 4H), 2.75 (t, J=7.2 Hz, 2H), 3.97 (t, J=7.2Hz, 2H), 4.75-4.84 (m, 1H); ESI-MS m/z: 740.6 [M+H]⁺.

Example 41: Synthesis of Compound 41

Referring to the method of Example 40, compound 41 was prepared as anoily product: 31.1 mg.

¹H NMR (400 MHz, CDCl₃): δ ppm 0.86-0.89 (m, 6H), 1.10 (s, 6H), 1.15 (s,6H), 1.08-1.31 (m, 34H), 1.41-1.61 (m, 14H), 1.74-1.82 (m, 2H),2.17-2.35 (m, 10H), 2.85 (t, J=7.2 Hz, 2H), 4.03 (t, J=7.2 Hz, 2H),4.82-4.87 (m, 1H); ESI-MS m/z: 726.6 [M+H]⁺.

Example 42: Synthesis of Compound 42

Referring to the method of Example 40, compound 42 was prepare as anoily product: 30.9 mg.

¹H NMR (400 MHz, CDCl₃): δ ppm 0.77-0.82 (m, 6H), 1.05 (s, 6H), 1.10 (s,6H), 1.11-1.28 (m, 31H), 1.33-1.42 (m, 9H), 1.47-1.59 (m, 2H), 1.73-1.81(m, 2H), 2.08-2.14 (m, 2H), 2.21-2.33 (m, 10H), 3.97 (t, J=7.2 Hz, 2H),4.55 (m, 2H), 4.72-4.81 (m, 1H); ESI-MS m/z: 706.6 [M+H]⁺.

Example 43: Synthesis of Compound 43

Referring to the method of Example 26, compound 43 was prepared as anoily product: 31.3 mg.

¹H NMR (400 MHz, CDCl₃): δ ppm 0.80 (m, 6H), 1.05 (s, 12H), 1.08-1.28(m, 34H), 1.36-1.47 (m, 8H), 1.49-1.58 (m, 2H), 1.73-1.82 (m, 2H),1.98-2.07 (m, 2H), 2.21-2.38 (m, 8H), 3.97 (t, J=7.2 Hz, 2H), 4.53 (d,J=7.2 Hz, 2H), 4.72-4.78 (m, 1H), 5.41-5.59 (m, 2H); ESI-MS m/z: 708.6[M+H]⁺.

Example 44: Synthesis of Compound 44

Referring to the method of Example 40, compound 44 was prepared as anoily product: 33.1 mg.

¹H NMR (400 MHz, CDCl₃): δ ppm 0.85 (m, 9H), 1.13 (s, 12H), 1.14-1.33(m, 46H), 1.37-1.59 (m, 16H), 1.78-1.87 (m, 2H), 2.17-2.35 (m, 10H),4.03 (t, J=6.8 Hz, 2H), 4.79-4.88 (m, 2H); ESI-MS m/z: 822.8 [M+H]⁺.

Example 45: Synthesis of Compound 45

n-Nonanoic acid (3.0 g, 19 mmol) was added to 50 mL of anhydroustetrahydrofuran and the reaction solution was cooled to 0° C. in an icebath. Sodium hydride (836 mg, 20.9 mmol) and LDA (49.4 mL, 24.7 mmol)were added to the reaction solution, and the reaction solution wasstirred at 0° C. for 1 hour. Then 1-iodoheptane was added dropwise tothe reaction system. The ice bath was removed, then the mixture wasreacted at room temperature for 12 h. The reaction solution was quenchedby pouring the reaction solution into saturated ammonium chloridesolution, and extracted with ethyl acetate. The organic phase wascollected, dried over anhydrous sodium sulfate, and filtered. Thefiltrate was collected, and concentrated to remove the solvent to givethe crude product, which was purified by silica gel column to give 2.0 gof compound 2-heptylnonanoic acid.

The 2-heptylnonanoic acid (2.0 g, 7.8 mmo) obtained in the previous stepwas dissolved in 30 mL of anhydrous tetrahydrofuran, and lithiumtetrahydroaluminum (593 mg, 15.6 mmol) was added to the reactionsolution. The reaction system was heated to 80° C. to react for 2 hours.The reaction solution was cooled to room temperature, quenched bypouring the reaction solution into saturated ammonium chloride solution,and extracted with ethyl acetate. The organic phase was collected, driedover anhydrous sodium sulfate, and filtered. The filtrate was collected,and concentrated to remove the solvent to give the crude product, whichwas purified by silica gel column to give 1.3 g of compound 45-1.

Then referring to the method of Example 40, compound 45 was prepared asan oily product: 31.6 mg.

¹H NMR (400 MHz, CDCl₃): δ ppm 0.88 (t, J=6.8 Hz, 9H), 1.14 (s, 12H),1.15-1.26 (m, 47H), 1.47-1.50 (m, 8H), 1.57-1.62 (m, 4H), 1.79-1.81 (m,2H), 2.25 (s, 6H), 2.32 (t, J=7.2 Hz, 4H), 3.93 (d, J=5.6 Hz, 2H), 4.03(t, J=7.2 Hz, 2H), 4.81-4.87 (m, 1H); ESI-MS m/z: 808.7 [M+H]⁺.

Example 46: Synthesis of Compound 46

Referring to the method of Example 40, compound 46 was prepared as anoily product: 32.6 mg.

¹H NMR (400 MHz, CDCl₃): δ ppm 0.88 (t, J=7.2 Hz, 9H), 1.14 (s, 12H),1.15-1.28 (m, 37H), 1.47-1.59 (m, 18H), 1.75-1.84 (m, 2H), 2.24-2.35 (m,10H), 3.95 (d, J=5.6 Hz, 2H), 4.03 (t, J=6.8 Hz, 2H), 4.80-4.87 (m, 1H);ESI-MS m/z: 780.7 [M+H]⁺.

Example 47: Synthesis of Compound 47

Referring to the method of Example 7, compound 47 was prepared as anoily product: 33.1 mg.

¹H NMR (400 MHz, CDCl₃): δ ppm 0.81 (t, J=6.8 Hz, 12H), 1.08 (s, 12H),1.09-1.24 (m, 56H), 1.40-1.61 (m, 14H), 1.67-1.72 (m, 2H), 2.17 (s, 6H),2.19-2.28 (m, 4H), 3.88 (d, J=5.6 Hz, 4H), 4.74-4.80 (m, 1H); ESI-MSm/z: 906.8 [M+H]⁺.

Example 48: Synthesis of Compound 48

Referring to the method of Example 7, compound 48 was prepared as anoily product: 34.8 mg.

¹H NMR (400 MHz, CDCl₃): δ ppm 0.81 (t, J=7.2 Hz, 12H), 1.08 (s, 12H),1.09-1.23 (m, 48H), 1.37-1.64 (m, 14H), 1.67-1.73 (m, 2H), 2.15 (s, 6H),2.20-2.37 (m, 4H), 3.88 (d, J=5.6 Hz, 4H), 4.74-4.89 (m, 1H); ESI-MSm/z: 850.8 [M+H]⁺.

The compounds of Table 2 were synthesized using the methods of the aboveexamples, or similar methods using the corresponding intermediates.

TABLE 2

Example 90: Synthesis of Compound 90

Referring to the method of Example 1, compound 90 was prepared as anoily product: 40.5 mg.

¹H NMR (400 MHz, CDCl₃): δ ppm 0.81 (t, J=6.8 Hz, 6H), 1.08 (s, 12H),1.10-1.28 (m, 36H), 1.38-1.47 (m, 12H), 1.50-1.58 (m, 4H), 2.40 (m, 6H),2.58 (t, J=6.8 Hz, 2H), 3.59-3.65 (m, 4H), 3.97 (t, J=6.8 Hz, 4H),4.75-4.83 (m, 1H); ESI-MS m/z: 766.7 [M+H]⁺.

Example 91: Synthesis of Compound 91

Referring to the method of Example 1, compound 91 was prepared as anoily product: 32.2 mg.

¹H NMR (400 MHz, CDCl₃): δ ppm 0.88 (t, J=6.8 Hz, 6H), 1.15 (s, 12H),1.16-1.38 (m, 40H), 1.46 (m, 8H), 1.60 (m, 4H), 2.59 (m, 4H), 3.19 (s,2H), 3.76 (t, J=4.8 Hz, 4H), 4.04 (t, J=6.8 Hz, 4H), 4.91 (m, 1H);ESI-MS m/z: 752.7 [M+H]⁺.

Example 92: Synthesis of Compound 92

Referring to the method of Example 1, compound 92 was prepared as anoily product: 32 mg.

¹H NMR (400 MHz, CDCl₃): δ ppm 0.87 (t, J=6.8 Hz, 6H), 1.13 (s, 12H),1.28 (m, 42H), 1.46 (m, 8H), 1.45 (m, 4H), 1.76 (m, 4H), 2.50 (m, 4H),2.76 (m, 2H), 4.01 (t, J=6.8 Hz, 4H), 4.84 (m, 1H); ESI-MS m/z: 750.9[M+H]⁺.

Example 93: Synthesis of Compound 93

3-Bromopropanol (20 g, 144 mmol), trifluoromethanesulfonic anhydride(26.6 mL, 158 mmol) and pyridine (14.0 mL, 173 mmol) were added to around bottom flask containing 500 mL of dichloromethane. The mixture wasstirred at room temperature until the reaction materials were completelyconsumed by TLC monitoring. The reaction solution was quenched with 1 Mhydrochloric acid solution, and extracted with dichloromethane. Theorganic phase were combined, dried over anhydrous sodium sulfate, andfiltered to remove the sodium sulfate. The filtrate was collected. Thesolvent was removed using a rotary-evaporator to give 25 g of crudecompound 93-2, which was used directly for subsequent reactions withoutfurther purification.

3-3 (6.0 g, 10 mmol) and crude compound 93-2 (3.0 g, 11 mmol) were addedto a round bottom flask containing 50 mL of nitromethane, then2,6-di-tert-butylpyridine (3.37 mL, 15 mmol) was added to the reactionsolution. The reaction solution was warmed up to 95° C. to reactovernight. The reaction solution was cooled to room temperature. Thesolvent was removed using a rotary-evaporator to give the crude product.The crude product was then dissolved in dichloromethane, extracted afteradding saturated aqueous ammonium chloride. The organic phase werecollected and combined, dried over anhydrous sodium sulfate, andfiltered to remove the sodium sulfate. The filtrate was collected. Thesolvent was removed using a rotary-evaporator and then purified bysilica gel column to give compound 93-3 (2.3 g).

Compound 93-3 (251 mg, 0.35 mmol) and 2-ethylpiperidine (71 μL, 0.53mmol) were dissolved in 3.0 mL of anhydrous acetonitrile and anhydrouspotassium carbonate (73 mg, 0.53 mmol) was added to the reactionsolution. The mixture was warmed up to 80° C. to react for 6 hours. Thereaction solution was cooled to room temperature, quenched by addingsaturated aqueous ammonium chloride, and extracted with dichloromethane.The organic phase were collected and combined, dried over anhydroussodium sulfate, and filtered to remove the sodium sulfate. The filtratewas collected. The solvent was removed using a rotary-evaporator andthen purified by preparative high performance liquid chromatography togive compound 93 (82 mg).

¹H NMR (400 MHz, CDCl₃): δ ppm 0.72-0.91 (m, 9H), 1.08 (s, 12H),1.11-1.75 (m, 60H), 1.87-2.25 (m, 3H), 2.57-2.93 (m, 4H), 3.04-3.15 (m,2H), 3.32-3.45 (m, 2H), 3.98 (d, J=6.8 Hz, 4H); ESI-MS m/z: 750.6[M+H]⁺.

Example 94: Synthesis of Compound 94

Referring to the method of Example 93, compound 94 was prepared as anoily product: 79.2 mg.

¹H NMR (400 MHz, CDCl₃): δ ppm 0.82 (t, J=7.2 Hz, 6H), 1.09 (s, 12H),1.11-1.34 (m, 44H), 1.52 (m, 14H), 2.45-2.74 (m, 6H), 3.07 (m, 1H), 3.38(m, 2H), 3.94 (t, J=6.8 Hz, 4H); ESI-MS m/z: 736.6 [M+H]⁺.

The compounds of Table 3 were synthesized using the methods of the aboveexamples, or similar methods using the corresponding intermediates.

TABLE 3

Example 97: Synthesis of Compound 97

To a round bottom flask were added CuCl (989 mg, 9.99 mmol) and 160 mLTHF, and the reaction system was cooled to −30° C. Then3-butenylmagnesium bromide (1 M, 299 mL) was added. 160 mL of solutionof compound 97-1 (40.0 g, 199 mmol) in tetrahydrofuran was slowly addedto the reaction system. After the dropwise addition was completed, thereaction system was warmed up to room temperature and stirred to reactfor another 2 hours. After the reaction material 97-1 was reactedcompletely by TLC monitoring, the reaction solution was quenched with300 mL of saturated aqueous ammonium chloride, and extracted with ethylacetate. The organic phases were combined, dried over anhydrous sodiumsulfate, and filtered. The filtrate was concentrated to dryness to givethe crude product. The crude was purified by silica gel column to givecompound 97-2 (45.0 g).

Compound 97-2 (42.0 g, 164 mmol) was dissolved in 400 mL of DMSO, and 4mL of water and LiCl (27.8 g, 655 mmol) were added to the reactionsolution. Then the reaction system was heated to 180° C. and stirreduntil the reactant 97-2 was reacted completely by TLC monitoring. Thereaction system was cooled to room temperature, then poured into waterand extracted with ethyl acetate. The organic phases were combined,dried over anhydrous sodium sulfate, and filtered. The filtrate wasconcentrated to dryness to give the crude product 97-3 (31.0 g), whichwas used directly in the next reaction without further purification.

Crude product 97-3 (30.0 g, 163 mmol) was dissolved in 240 mL oftetrahydrofuran and BH₃·THF (1 M, 244 mL) was added dropwise to thereaction solution in an ice bath. Then the mixture was warmed up to roomtemperature and stirred for 2 h. The reaction system was then cooled to0° C. in an ice bath and methanol (13.2 mL, 325 mmol), Br₂ (8.39 mL, 163mmol) and sodium methoxide (43.9 g, 244 mmol) were added sequentially.

The mixture was warmed up to room temperature and stirred for another 1h. The reaction solution was quenched with cold saturated aqueousammonium chloride solution and extracted with ethyl acetate. The organicphases were combined, dried over anhydrous sodium sulfate, and filtered.The filtrate was concentrated to dryness to give the crude product,which was purified by silica gel column to give compound 97-4 (14.0 g).

Then referring to the method of Example 1, compound 97 was prepared asan oily product: 31.6 mg.

¹H NMR (400 MHz, CDCl₃): δ ppm 0.84-0.90 (m, 6H), 0.93-1.01 (m, 12H),1.20-1.31 (m, 32H), 1.45-1.62 (m, 16H), 2.17 (s, 4H), 2.19-2.44 (m, 8H),3.99-4.08 (m, 4H), 4.81-4.91 (m, 1H); ESI-MS m/z: 710.7 [M+H]⁺.

Example 98: Synthesis of Compound 98

Referring to the method of Example 97, compound 98 was prepared as anoily product: 31.0 mg.

¹H NMR (400 MHz, CDCl₃): δ ppm 0.88 (t, J=6.8 Hz, 9H), 0.97 (s, 12H),1.25-1.39 (m, 38H), 1.45-1.59 (m, 10H), 1.79 (m, 2H), 2.06-2.13 (m, 2H),2.18 (m, 4H), 2.20-2.39 (m, 9H), 3.94 (d, J=5.6 Hz, 2H), 4.59 (d, J=6.8Hz, 2H), 4.82-4.87 (m, 1H), 5.48-5.53 (m, 1H), 5.60-5.64 (m, 1H); ESI-MSm/z: 792.7 [M+H]⁺.

Example 99: Synthesis of Compound 99

A solution of compound 1-1 (100 g, 979 mmol) in tetrahydrofuran (800 mL)was cooled to −40° C. LDA (2 M, 490 mL) was added slowly dropwise to thesolution and the mixture was stirred for another 1 h after completion ofthe dropwise addition. A solution of 1-2 (315 g, 1.37 mol) intetrahydrofuran (100 mL) was added dropwise to the reaction system atthe same temperature and the reaction system was stirred overnight. Thereaction system was quenched with saturated aqueous ammonium chloride,and extracted with ethyl acetate. The organic phases were combined,dried over anhydrous sodium sulfate, and filtered. The filtrate wasconcentrated to dryness to give the crude product. The crude product waspurified by silica gel column to give compound 1-3 (115 g). ¹H NMR (400MHz, CDCl₃): δ ppm 1.06-1.11 (m, 6H), 1.13-1.22 (m, 2H), 1.29-1.39 (m,2H), 1.42-1.49 (m, 2H), 1.73-1.82 (m, 2H), 3.28-3.40 (m, 2H), 3.55-3.66(m, 3H).

A solution of compound 1-3 (100 g, 398 mmol), TsCH₂CN (38.9 g, 199 mmol)and TBAI (14.7 g, 39.8 mmol) in dimethyl sulfoxide (800 mL) was cooledto 0° C., and sodium hydride (20.7 g, 517 mmol, 60% purity) was addedslowly in batches. The mixture was reacted at room temperatureovernight. The reaction system was quenched with saturated aqueoussodium chloride solution and extracted with ethyl acetate. The organicphases were combined, dried over anhydrous sodium sulfate, and filtered.The filtrate was concentrated to dryness to give 115 g of crude compound1-4, which was used directly in the next reaction without isolation andpurification.

To a solution of compound 1-4 crude (110 g, 205 mmol) in dichloromethane(880 mL) was added 330 mL of concentrated hydrochloric acid, and themixture was reacted at room temperature for 2 h. The complete reactionof the substrate was monitored by TLC. The reaction system was quenchedwith saturated aqueous ammonium chloride solution and extracted withethyl acetate. The organic phases were combined, dried over anhydroussodium sulfate, and filtered. The filtrate was concentrated to drynessto give the crude product. The crude product was purified by silica gelcolumn to give compound 1-5 (30.0 g, 80.9 mmol, 39.4%).

TMSOK (11.0 g, 86.4 mmol) was added to a solution of compound 1-5 (8.0g, 21.6 mmol) in tetrahydrofuran (35.0 mL) at room temperature, and thereaction system was heated to 70° C. with stirring. The completeconsumption of reaction materials was monitored by TLC. The reactionsolution was cooled to room temperature, and the organic solvent wasremoved by rotary evaporation. The crude product was added to 20 mL ofwater and extracted with dichloromethane. The aqueous layer wascollected, and the solution was adjusted to a pH of <5 with 1 Mhydrochloric acid. The solution was extracted with dichloromethane. Theorganic phases were combined, dried over anhydrous sodium sulfate, andfiltered. The filtrate was collected and concentrated to give compound1-6 (7.0 g). ¹H NMR (400 MHz, CDCl₃): δ ppm 1.03 (s, 12H), 1.08-1.17 (m,8H), 1.34-1.45 (m, 8H), 2.21 (t, J=7.2 Hz, 4H).

Potassium carbonate (482 mg, 3.48 mmol) was added to a solution ofcompound 1-6 (294 mg, 0.87 mmol) and 1-7 (771 mg, 3.48 mmol) in DMF,then the reaction was warmed up to 60° C. for 6 h. The completedisappearance of reactant 1-6 was monitored. The mixture was cooled toroom temperature. The reaction system was quenched with saturatedaqueous sodium chloride solution and extracted with ethyl acetate. Theorganic phases were combined, dried over anhydrous sodium sulfate, andfiltered. The filtrate was concentrated to dryness to give the crudeproduct. The crude was purified by silica gel column to give compound1-8 (325 mg).

Compound 1-8 (325 mg) was dissolved in 4.0 mL of methanol and sodiumborohydride (30 mg, 0.84 mmol) was added to the reaction system. Themixture was reacted at room temperature. The complete disappearance ofthe reactants was monitored by TLC. The reaction system was quenchedwith saturated aqueous sodium chloride solution and extracted withdichloromethane. The organic phases were combined, dried over anhydroussodium sulfate, and filtered. The filtrate was concentrated to drynessto give crude compound 1-9 (260 mg), which was used directly in the nextreaction without purification.

Crude compound 1-9 (250 mg, 0.40 mmol), 1-11 (35.9 mg, 0.60 mmol), EDCI(230 mg, 1.20 mmol), triethylamine (0.17 mL, 1.20 mmol) and DMAP (49 mg,0.40 mmol) were dissolved in 5.0 mL of dichloromethane, and the reactionsolution was stirred to react at room temperature for 12 h. The reactionsolution was quenched with saturated aqueous sodium chloride andextracted with dichloromethane. The organic phases were combined, driedover anhydrous sodium sulfate, and filtered. The organic phase wascollected and the organic solvent was removed using a rotary-evaporatorto give the crude product, which was purified by preparative highperformance liquid chromatography to give compound 99 (31.6 mg)

¹H NMR (400 MHz, CDCl₃): δ ppm 0.86 (t, J=6.8 Hz, 6H), 1.13 (s, 12H),1.25 (m, 43H), 1.46 (m, 8H), 1.57 (m, 4H), 1.84 (m, 4H), 2.33 (s, 3H),2.86 (m, 2H), 4.01 (m, 4H), 4.81 (m, 1H); ESI-MS m/z: 751.0 [M+H]⁺.

Example 100: Synthesis of Compound 100

Referring to the method of Example 99, compound 100 was prepared as anoily product: 33.5 mg.

¹H NMR (400 MHz, CDCl₃): δ ppm 0.81 (t, J=6.8 Hz, 6H), 1.08 (s, 12H),1.11-1.31 (m, 30H), 1.41 (m, 9H), 1.54 (m, 5H), 1.65-1.77 (m, 2H),1.78-1.98 (m, 4H), 2.20 (m, 4H), 2.74 (m, 2H), 3.97 (t, J=6.8 Hz, 4H),4.71-4.85 (m, 1H); ESI-MS m/z: 694.6 [M+H]⁺.

Example 101: Synthesis of Compound 101

Referring to the method of Example 99, compound 101 was prepared as anoily product: 30.8 mg.

¹H NMR (400 MHz, CDCl₃): δ ppm 0.81 (t, J=6.8 Hz, 6H), 0.96 (d, J=6.8Hz, 6H), 1.08 (s, 12H), 1.11-1.31 (m, 32H), 1.35-1.46 (m, 8H), 1.54 (m,4H), 1.59-1.74 (m, 4H), 2.01-2.13 (m, 3H), 2.62 (m, 1H), 2.77 (m, 2H),3.97 (t, J=6.8 Hz, 4H), 4.71-4.83 (m, 1H); ESI-MS m/z: 722.6 [M+H]⁺.

Example 102: Synthesis of Compound 102

Referring to the method of Example 99, compound 102 was prepared as anoily product: 32.4 mg.

¹H NMR (400 MHz, CDCl₃): δ ppm 0.90 (t, J=6.8 Hz, 6H), 1.17 (s, 12H),1.20-1.41 (m, 34H), 1.44-1.55 (m, 8H), 1.57-1.69 (m, 5H), 1.73-1.86 (m,3H), 1.92 (m, 2H), 2.02 (m, 2H), 2.21-2.33 (m, 4H), 2.82-2.85 (m, 2H),4.06 (t, J=6.8 Hz, 4H), 4.84-4.90 (m, 1H); ESI-MS m/z: 722.6 [M+H]⁺.

Example 103: Synthesis of Compound 103

Referring to the method of Example 99, compound 103 was prepared as anoily product: 32.8 mg.

¹H NMR (400 MHz, CDCl₃): δ ppm 0.81 (t, J=6.8 Hz, 6H), 0.96 (d, J=6.8Hz, 6H), 1.08 (s, 12H), 1.11-1.33 (m, 34H), 1.34-1.47 (m, 8H), 1.54 (m,5H), 1.60-1.75 (m, 3H), 1.83 (m, 2H), 2.03-2.24 (m, 3H), 2.56-2.79 (m,3H), 3.97 (t, J=6.8 Hz, 4H), 4.74-4.81 (m, 1H); ESI-MS m/z: 750.6[M+H]⁺.

Example 104: Synthesis of Compound 104

Compound 1-6 (448 mg, 1.3 mmol) was dissolved in 5.0 mL ofdichloromethane, and the reaction system was cooled to 0° C. in an icebath. DMF (10 μL, 0.13 mmol) was added and oxalyl chloride (0.44 mL, 5.2mmol) was then added dropwise to the reaction solution. The ice bath wasremoved after the dropwise addition was completed and the mixture wasstirred for 1 h at room temperature. The solvent was removed using arotary-evaporator to give acyl chloride crude product (330 mg) as anoil, which was used directly in the next reaction step.

1-Decanethiol 33-1 (455 mg, 2.61 mmol) was added to a solution of crudeacyl chloride (330 mg, 0.87 mmol) in DCE (3.0 mL), and the reaction washeated to 70° C. to react overnight. The reaction solution was cooled toroom temperature and the solvent was removed using a rotary-evaporatorto give the crude product, which was purified by silica gel column togive compound 33-2 (400 mg). ¹H NMR (400 MHz, CDCl₃): δ ppm 0.84-0.87(m, 6H), 1.14-1.18 (m, 12H), 1.20-1.28 (m, 36H), 1.48-1.55 (m, 12H),2.33 (t, J=7.2 Hz, 4H), 2.79 (t, J=7.2 Hz, 4H).

Compound 33-2 (300 mg, 0.46 mmol) was dissolved in 3.0 mL of methanoland NaBH₄ (52.5 mg, 1.38 mmol) was added in batches. The reactionsolution was stirred under nitrogen atmosphere at room temperature for 2h. The complete disappearance of the reaction material was monitored byTLC. The reaction solution was quenched by adding saturated ammoniumchloride solution, and extracted with ethyl acetate. The organic phaseswere combined, dried over anhydrous sodium sulfate, and filtered. Thefiltrate was collected and concentrated to give 300 mg of crude compound33-3, which was directly used in the next reaction step without furtherpurification.

Crude compound 33-3 (300 mg, 0.46 mmol), 1-11 (98.8 mg, 0.69 mmol), EDCI(264.5 mg, 1.38 mmol), triethylamine (0.19 mL, 1.38 mmol) and DMAP (56.2mg, 0.46 mmol) were dissolved in 8.0 mL of dichloromethane, and thereaction solution was stirred at room temperature until the reactionmaterial 33-3 was completely consumed. The reaction solution wasquenched with saturated aqueous sodium chloride and extracted withdichloromethane. The organic phases were combined, dried over anhydroussodium sulfate, and filtered. The organic phase was collected, and theorganic solvent was removed using a rotary-evaporator. The crude productwas purified by preparative high performance liquid chromatography togive the compound 104 (67.3 mg).

¹H NMR (400 MHz, CDCl₃): δ ppm 0.81 (t, J=6.8 Hz, 6H), 1.08 (s, 12H),1.09-1.31 (m, 42H), 1.35-1.51 (m, 14H), 1.61-2.25 (m, 8H), 2.73 (t,J=7.2 Hz, 4H), 4.77 (m, 1H); ESI-MS m/z: 782.7 [M+H]⁺.

Example 105: Synthesis of Compound 105

Referring to the method of Example 104, compound 105 was prepared as anoily product: 27.1 mg.

¹H NMR (400 MHz, CDCl₃): δ ppm 0.85-0.89 (m, 6H), 1.02 (br d, J=6.4 Hz,6H), 1.18 (s, 12H), 1.20-1.40 (m, 40H), 1.42-1.59 (m, 12H), 1.64-1.83(m, 3H), 1.87-1.93 (m, 2H), 2.11-2.23 (m, 3H), 2.66-2.94 (m, 6H),4.72-4.94 (m, 1H); ESI-MS m/z: 810.6 [M+H]⁺.

Example 106: Synthesis of Compound 106

Referring to the method of Example 104, compound 106 was prepared as anoily product: 38.4 mg.

¹H NMR (400 MHz, CDCl₃): δ ppm 0.88 (t, J=7.2 Hz, 6H), 1.17 (s, 12H),1.15-1.34 (m, 36H), 1.43-1.57 (m, 15H), 1.69-2.09 (m, 5H), 2.27-2.34 (m,3H), 2.77-2.86 (m, 5H), 4.78-4.85 (m, 1H); ESI-MS m/z: 754.6 [M+H]⁺.

Example 107: Synthesis of Compound 107

Referring to the method of Example 104, compound 107 was prepared as anoily product: 39 mg.

¹H NMR (400 MHz, CDCl₃): δ ppm 0.88 (t, J=6.8 Hz, 6H), 1.05 (d, J=6.8Hz, 6H), 1.16 (s, 12H), 1.12-1.35 (m, 34H), 1.37-1.55 (m, 15H),1.62-1.92 (m, 4H), 2.15-2.19 (m, 3H), 2.71-2.93 (m, 6H), 4.78-4.85 (m,1H); ESI-MS m/z: 782.6 [M+H]⁺.

Example 108: Synthesis of Compound 108

Referring to the method of Example 104, compound 108 was prepared as anoily product: 43.8 mg.

¹H NMR (400 MHz, CDCl₃): δ ppm 0.88 (t, J=6.80 Hz, 6H), 1.18 (s, 12H),1.20-1.39 (m, 38H), 1.40-1.62 (m, 14H), 1.66-1.86 (m, 3H), 1.89-2.10 (m,2H), 2.19-2.27 (m, 3H), 2.28 (br s, 2H), 2.79-2.83 (m, 4H), 4.79-4.88(m, 1H); ESI-MS m/z: 768.5 [M+H]⁺.

Example 109: Synthesis of Compound 109

Referring to the method of Example 104, compound 109 was prepared as anoily product: 44.8 mg.

¹H NMR (400 MHz, CDCl₃): δ ppm 0.86-0.89 (m, 6H), 1.18 (s, 15H),1.23-1.37 (m, 36H), 1.46-1.54 (m, 14H), 1.76-1.93 (m, 4H), 2.11-2.20 (m,1H), 2.24-2.28 (m, 2H), 2.54-2.71 (m, 2H), 2.81 (d, J=7.2 Hz, 4H),3.08-3.24 (m, 2H), 4.79-4.88 (m, 1H); ESI-MS m/z: 782.6 [M+H]⁺.

Example 110: Synthesis of Compound 110

Referring to the method of Example 104, compound 110 was prepared as anoily product: 34.4 mg.

¹H NMR (400 MHz, CDCl₃): δ ppm 0.81 (t, J=7.2 Hz, 6H), 1.12 (s, 12H),1.14-1.27 (m, 34H), 1.44-1.48 (m, 12H), 1.66-1.77 (m, 7H), 2.05-2.24 (m,4H), 2.53 (m, 2H), 2.75 (t, J=7.2 Hz, 4H), 2.90-2.92 (m, 2H), 3.57 (t,J=5.2 Hz, 2H), 4.74-4.80 (m, 1H); ESI-MS m/z: 798.6 [M+H]⁺.

Example 111: Synthesis of Compound 111

Referring to the method of Example 104, compound 111 was prepared as anoily product: 31.4 mg.

¹H NMR (400 MHz, CDCl₃): δ ppm 0.92 (t, J=6.8 Hz, 9H), 1.19 (s, 12H),1.20-1.35 (m, 43H), 1.47-1.55 (m, 9H), 1.54-1.82 (m, 12H), 2.07-2.37 (m,7H), 2.94-3.01 (m, 2H), 3.98 (d, J=6.8 Hz, 2H), 4.07 (t, J=6.8 Hz, 2H),4.84-4.91 (m, 1H); ESI-MS m/z: 806.7 [M+H]⁺.

Example 112: Synthesis of Compound 112

Referring to the method of Example 104, compound 112 was prepared as anoily product: 24.4 mg.

¹H NMR (400 MHz, CDCl₃): δ ppm 0.80-0.83 (m, 9H), 1.08 (s, 12H),1.10-1.35 (m, 28H), 1.41-1.57 (m, 28H), 1.65-1.75 (m, 4H), 1.95-2.10 (m,2H), 2.16 (d, J=6.4 Hz, 2H), 2.30 (s, 3H), 2.73-2.91 (m, 4H), 3.87 (d,J=5.6 Hz, 2H), 4.75-4.79 (m, 1H); ESI-MS m/z: 822.7 [M+H]⁺.

Example 113: Synthesis of Compound 113

Referring to the method of Example 110, compound 113 was prepared as anoily product: 31.1 mg.

¹H NMR (400 MHz, CDCl₃): δ ppm 0.81 (t, J=7.2 Hz, 6H), 1.08 (s, 12H),1.10-1.24 (m, 36H), 1.36-1.43 (m, 8H), 1.48-1.54 (m, 6H), 1.64-1.72 (m,6H), 2.05 (t, J=6.8 Hz, 1H), 2.15 (d, J=6.8 Hz, 2H), 2.47 (t, J=5.6 Hz,2H), 2.82-2.89 (m, 2H), 3.54 (t, J=5.6 Hz, 2H), 3.97 (t, J=6.8 Hz, 4H),4.73-4.79 (m, 1H); ESI-MS m/z: 766.6 [M+H]⁺.

Example 114: Synthesis of Compound 114

Referring to the method of Example 110, compound 114 was prepared as anoily product: 32.7 mg.

¹H NMR (400 MHz, CDCl₃): δ ppm 0.85-0.88 (m, 9H), 1.07 (s, 12H),1.09-1.35 (m, 46H), 1.41-1.58 (m, 13H), 1.97-2.25 (m, 3H), 2.32 (d,J=5.6 Hz, 2H), 2.83-2.86 (m, 2H), 3.17-3.19 (m, 2H), 3.78-3.81 (d, J=7.2Hz, 2H), 3.92 (d, J=5.6 Hz, 2H), 4.01 (t, J=6.4 Hz, 2H), 4.10 (m, 1H),4.81-4.86 (m, 1H); ESI-MS m/z: 836.7 [M+H]⁺.

Example 115: Synthesis of Compound 115

Referring to the method of Example 104, compound 115 was prepared as anoily product: 31.0 mg.

¹H NMR (400 MHz, CDCl₃): δ ppm 0.87-0.91 (m, 9H), 1.14-1.37 (m, 51H),1.49-1.60 (m, 12H), 1.75-1.81 (m, 2H), 2.21-2.26 (m, 2H), 2.28 (s, 6H),2.32-2.36 (m, 4H), 4.03 (t, J=6.4 Hz, 2H), 4.65 (s, 2H), 4.82-4.88 (m,1H); ESI-MS m/z: 790.6 [M+H]⁺.

Example 116: Synthesis of Compound 116

Referring to the method of Example 104, compound 116 was prepared as anoily product: 31.3 mg.

¹H NMR (400 MHz, CDCl₃): δ ppm 0.80-0.83 (m, 9H), 1.07-1.27 (m, 51H),1.40-1.45 (m, 12H), 1.70-1.81 (m, 2H), 2.13-2.36 (m, 12H), 3.87 (d,J=5.6 Hz, 2H), 4.57 (s, 2H), 4.74-4.80 (m, 1H); ESI-MS m/z: 790.6[M+H]⁺.

Example 117: Synthesis of Compound 117

Referring to the method of Example 104, compound 117 was prepared as anoily product: 35.9 mg.

¹H NMR (400 MHz, CDCl₃): δ ppm 0.90 (t, J=6.8 Hz, 12H), 1.15 (s, 12H),1.16-1.33 (m, 38H), 1.48-1.53 (m, 8H), 1.82-1.86 (m, 2H), 2.18-2.20 (m,4H), 2.30-2.42 (m, 10H), 4.65 (m, 4H), 4.82-4.88 (m, 1H); ESI-MS m/z:814.6 [M+H]⁺.

Example 118: Synthesis of Compound 118

Referring to the method of Example 104, compound 118 was prepared as anoily product: 32.0 mg.

¹H NMR (400 MHz, CDCl₃): δ ppm 0.87-0.90 (m, 9H), 1.15-1.32 (m, 50H),1.40-1.61 (m, 16H), 1.76-1.84 (m, 2H), 2.23 (s, 6H), 2.29-2.34 (m, 6H),4.04 (t, J=6.8 Hz, 2H), 4.66 (d, J=2.0 Hz, 1H), 4.83-4.87 (m, 1H);ESI-MS m/z: 804.6 [M+H]⁺.

Example 119: Synthesis of Compound 119

Referring to the method of Example 104, compound 119 was prepared as anoily product: 34.8 mg.

¹H NMR (400 MHz, CDCl₃): δ ppm 0.91-0.94 (m, 9H), 1.21-1.40 (m, 48H),1.51-1.57 (m, 12H), 1.61-1.86 (m, 5H), 2.23 (m, 2H), 2.31 (s, 6H),2.35-2.39 (m, 2H), 2.85 (t, J=7.2 Hz, 2H), 4.67 (t, J=2.0 Hz, 1H),4.84-4.90 (m, 1H); ESI-MS m/z: 792.6 [M+H]⁺.

Example 120: Synthesis of Compound 120

Referring to the method of Example 104, compound 120 was prepared as anoily product: 34.5 mg.

¹H NMR (400 MHz, CDCl₃): δ ppm 0.89 (t, J=6.8 Hz, 9H), 1.15-1.31 (m,48H), 1.47-1.57 (m, 16H), 1.75-1.85 (m, 4H), 2.19-2.41 (m, 11H), 4.07(t, J=6.8 Hz, 2H), 4.65 (t, J=2.0 Hz, 2H), 4.27-4.88 (m, 1H); ESI-MSm/z: 804.6 [M+H]⁺.

Example 121: Synthesis of Compound 121

Referring to the method of Example 104, compound 121 was prepared as anoily product: 33.8 mg.

¹H NMR (400 MHz, CDCl₃): δ ppm 0.91-0.95 (m, 9H), 1.20-1.43 (m, 46H),1.47-1.57 (m, 10H), 1.63-1.85 (m, 6H), 2.29-2.40 (m, 12H), 2.85 (t,J=7.2 Hz, 2H), 4.68 (s, 2H), 4.84-4.90 (m, 1H); ESI-MS m/z: 764.6[M+H]⁺.

Example 122: Synthesis of Compound 122

Referring to the method of Example 104, compound 122 was prepared as anoily product: 33.7 mg.

¹H NMR (400 MHz, CDCl₃): δ ppm 0.81 (t, J=6.8 Hz, 9H), 1.08-1.31 (m,46H), 1.40-1.58 (m, 17H), 1.68-1.73 (m, 2H), 2.17 (s, 6H), 2.25 (t,J=7.2 Hz, 4H), 3.87 (d, J=5.6 Hz, 2H), 3.97 (t, J=6.8 Hz, 2H), 4.73-4.80(m, 1H); ESI-MS m/z: 752.7 [M+H]⁺.

Example 123: Synthesis of Compound 123

Referring to the method of Example 104, compound 123 was prepared as anoily product: 35.2 mg.

¹H NMR (400 MHz, CDCl₃): δ ppm 0.81 (t, J=6.8 Hz, 9H), 1.08 (s, 12H),1.10-1.33 (m, 36H), 1.40-1.57 (m, 17H), 1.68-1.73 (m, 2H), 2.17 (s, 6H),2.25 (t, J=7.2 Hz, 4H), 3.87 (d, J=5.6 Hz, 2H), 3.97 (t, J=6.8 Hz, 2H),4.73-4.79 (m, 1H); ESI-MS m/z: 766.7 [M+H]⁺.

Example 124: Synthesis of Compound 124

Referring to the method of Example 104, compound 124 was prepared as anoily product: 33.4 mg.

¹H NMR (400 MHz, CDCl₃): δ ppm 0.89 (t, J=6.8 Hz, 9H), 1.15 (s, 12H),1.18-1.37 (m, 39H), 1.47-1.65 (m, 16H), 2.28 (s, 6H), 2.29-2.35 (m, 4H),3.95 (d, J=5.6 Hz, 2H), 4.04 (t, J=6.8 Hz, 2H), 4.79-4.86 (m, 1H);ESI-MS m/z: 766.6 [M+H]⁺.

Example 125: Synthesis of Compound 125

Referring to the method of Example 104, compound 125 was prepared as anoily product: 31.1 mg.

¹H NMR (400 MHz, CDCl₃): δ ppm 0.89 (t, J=6.8 Hz, 9H), 1.15 (s, 12H),1.18-1.37 (m, 48H), 1.48-1.51 (m, 8H), 1.60-1.63 (m, 3H), 1.80-1.88 (m,2H), 2.32-2.41 (m, 10H), 3.95 (d, J=5.6 Hz, 2H), 4.04 (t, J=6.8 Hz, 2H),4.81-4.88 (m, 1H); ESI-MS m/z: 808.7 [M+H]⁺.

Example 126 Synthesis of Compound 126

Referring to the method of Example 104, compound 126 was prepared as anoily product: 35.1 mg.

¹H NMR (400 MHz, CDCl₃): δ ppm 0.89 (t, J=6.8 Hz, 9H), 1.16 (s, 12H),1.18-1.37 (m, 48H), 1.48-1.65 (m, 15H), 2.32-2.43 (m, 10H), 3.95 (d,J=5.6 Hz, 2H), 4.05 (t, J=6.8 Hz, 2H), 4.81-4.89 (m, 1H); ESI-MS m/z:822.7 [M+H]⁺.

Example 127: Synthesis of Compound 127

A solution of compound 127-1 (100 g, 552.4 mmol) in anhydrous ether (800mL) was cooled to 0° C. in an ice bath, and methylmagnesium bromide (3 Min ether, 737 mL) was slowly added dropwise to the solution. After thedropwise addition was completed, the ice bath was removed and themixture was stirred to react for 4 h at room temperature. The reactionsystem was quenched with saturated ammonium chloride aqueous solution,and extracted with ether. The organic phases were combined, dried overanhydrous sodium sulfate, and filtered. The filtrate was concentrated todryness to give the crude product. The crude product was purified bysilica gel column to give compound 127-2 (100 g).

Compound 127-2 (42 g, 232 mmol), compound 127-3 (30.3 mL, 278 mmol),Cp*TiCl₃ (5.09 g, 23.2 mmol), zinc powder (45.5 g, 696 mmol), andtriethylchlorosilane (116.8 mL, 696 mmol) were added to a round bottomflask. Then anhydrous tetrahydrofuran (1200 mL) was added to thereaction system and the reaction was carried out under the protection ofargon gas. The reaction system was heated to 60° C. and stirred to reactfor 1 hour. The reaction system was quenched with saturated aqueoussodium chloride solution and extracted with ethyl acetate. The organicphases were combined, dried over anhydrous sodium sulfate, and filtered.The filtrate was concentrated to dryness to give crude product 1-4,which was purified by silica gel column to give compound 127-4 (21 g).

Compound TosMIC (7.03 g, 36 mmol) was dissolved in DMSO (200 mL), andNaH (4.32 g, 60%, 108 mmol) was added to the reaction system in batchesunder ice bath conditions. After the addition was completed, the icebath was removed and the mixture was reacted at room temperature foranother 1 h. Compound 127-4 (21 g, 79 mmol) and TBAI (1.33 g, 3.6 mmol)were added to the reaction system, and the mixture was stirred at roomtemperature overnight. The reaction system was quenched with saturatedaqueous sodium chloride solution and extracted with ethyl acetate. Theorganic phases were combined, dried over anhydrous sodium sulfate, andfiltered. The filtrate was concentrated to dryness to give crudecompound 127-5 (21.9 g), which was used directly in the next reactionstep without purification.

To a solution of crude compound 127-5 (21.9 g, 38.8 mmol) indichloromethane (350 mL) was added 200 mL of concentrated hydrochloricacid, and the mixture was reacted at room temperature for 2 h. Thecomplete reaction of the substrate was monitored by TLC. The reactionsystem was quenched with saturated aqueous ammonium chloride solutionand extracted with ethyl acetate. The organic phases were combined,dried over anhydrous sodium sulfate, and filtered. The filtrate wasconcentrated to dryness to give the crude product, which was purified bysilica gel column to give compound 127-6 (12.5 g).

Compound 127-6 (12.5 g, 31.4 mmol) was dissolved in ethanol (20mL)-water (40 mL), and NaOH (3.77 g, 94.2 mmol) was added to the mixedsolution in batches under ice bath conditions. After the addition wascompleted, the ice bath was removed and the mixture was stirred at roomtemperature. The complete consumption of the reaction materials wasmonitored by TLC. The organic solvent was removed by rotary evaporation,and the residue was extracted with dichloromethane. The aqueous layerwas collected, and the solution was adjusted to a pH of <5 with 1 Mhydrochloric acid. The solution was extracted with dichloromethane. Theorganic phases were combined, dried over anhydrous sodium sulfate, andfiltered. The filtrate was collected and concentrated to give compound127-7 (9.7 g).

DMF (17 μL, 0.22 mmol) was added to a solution of compound 127-7 (750mg, 2.19 mmol) in dichloromethane (10.0 mL) under ice bath conditions,and oxalyl chloride (0.77 mL, 8.76 mmol) was then added dropwise to thereaction solution. The ice bath was removed, and the mixture was stirredfor 1 h at room temperature. The solvent was removed using arotary-evaporator to give acyl chloride crude product, which was useddirectly in the next reaction step.

The above obtained acyl chloride crude product was dissolved in 10.0 mLof 1,2-dichloroethane, and then compound 127-8 (693 mg, 4.38 mmol) wasadded to the reaction solution. The mixture was stirred at roomtemperature until the substrate was reacted completely. The solvent wasremoved using a rotary-evaporator. The crude was purified by silica gelcolumn to give compound 127-9 (800 mg).

Compound 127-9 (800 mg, 1.29 mmol) was dissolved in 5.0 mL of methanoland sodium borohydride (146 mg, 3.87 mmol) was added to the reactionsystem. The mixture was reacted at room temperature. The completedisappearance of the reactants was monitored by TLC. The reaction systemwas quenched with saturated aqueous sodium chloride solution andextracted with dichloromethane. The organic phases were combined, driedover anhydrous sodium sulfate, and filtered. The filtrate wasconcentrated to dryness to give crude compound 127-10 (800 mg), whichwas used directly in the next reaction without purification.

Crude compound 127-10 (300 mg, 0.48 mmol), 4-dimethylaminobutyric acid(94.4 mg, 0.72 mmol), EDCI (276 mg, 1.44 mmol), triethylamine (0.21 mL,1.44 mmol) and DMAP (59 mg, 0.48 mmol) were dissolved in 5.0 mL ofdichloromethane, and the reaction solution was stirred to react at roomtemperature for 12 h. The reaction solution was quenched with saturatedaqueous sodium chloride and extracted with dichloromethane. The organicphases were combined, dried over anhydrous sodium sulfate, and filtered.The organic phase was collected, and the organic solvent was removedusing a rotary-evaporator. The crude product was purified by preparativehigh performance liquid chromatography to give the compound 127 (43.6mg)

¹H NMR (400 MHz, CD₃OD): δ ppm 0.77-0.93 (m, 28H), 1.08-1.74 (m, 38H),1.76-1.84 (m, 2H), 1.22-2.27 (m, 10H), 2.33-2.37 (m, 4H), 4.03-4.12 (m,4H), 4.92-4.97 (m, 1H); ESI-MS m/z: 738.6 [M+H]⁺.

Example 128: Synthesis of Compound 128

Referring to the method of Example 127, compound 128 was prepared as anoily product: 64.2 mg.

¹H NMR (400 MHz, CD₃OD): δ ppm 0.86 (s, 12H), 0.91 (t, J=6.8 Hz, 12H),1.22-1.37 (m, 48H), 1.51-1.61 (m, 14H), 1.78-1.86 (m, 2H), 2.24 (t,J=8.0 Hz, 4H), 2.30 (s, 6H), 2.37 (t, J=7.2 Hz, 2H), 2.43 (t, J=8.0 Hz,2H), 4.10 (t, J=6.8 Hz, 4H), 4.92-4.97 (m, 1H); ESI-MS m/z: 878.7[M+H]⁺.

Example 129: Synthesis of Compound 129

Referring to the method of Example 127, compound 129 was prepared as anoily product: 67.0 mg.

¹H NMR (400 MHz, CD₃OD): δ ppm 0.86 (s, 12H), 0.88-0.93 (m, 12H),1.12-1.40 (m, 52H), 1.49-1.56 (m, 8H), 1.59-1.66 (m, 4H), 1.77-1.84 (m,4H), 2.22-2.27 (m, 10H), 2.34-2.38 (m, 4H), 4.01 (t, J=6.8 Hz, 4H),4.91-4.97 (m, 1H); ESI-MS m/z: 906.8 [M+H]⁺.

COMPARATIVE EXAMPLES Synthesis of Comparative Compound 1 (D1)

D1 was prepared according to the method of Example 20, [M+H]⁺: 654.6. ¹HNMR (400 MHz, CDCl₃): δ ppm 0.77-0.86 (t, J=7.2 Hz, 6H), 1.15-1.30 (m,38H), 1.40-1.59 (m, 12H), 1.87-1.96 (m, 2H), 2.21 (t, J=7.2 Hz, 4H),2.28-2.37 (m, 2H), 2.40-2.50 (m, 5H), 2.56-2.67 (m, 2H), 3.92-4.07 (m,4H), 4.72-4.90 (m, 1H).

Synthesis of Comparative Compound 2 (D2)

D2 was prepared according to the method of Example 46, [M+H]⁺: 724.6. ¹HNMR (400 MHz, CDCl₃): δ ppm 0.89 (t, J=7.2 Hz, 9H), 1.21-1.30 (m, 44H),1.50-1.63 (m, 11H), 1.77-1.92 (m, 2H), 2.27-2.36 (m, 14H), 3.97 (d,J=5.6 Hz, 2H), 4.06 (t, J=6.8 Hz, 2H), 4.85-4.92 (m, 1H).

Pharmacological Assay

Assay Example 1: Preparation of Nanoparticles

Materials used for lipid nanoparticle assembly include: (1) ionizablelipid compounds: e.g., ionizable lipids designed and synthesized in thepresent disclosure or DLin-MC3-DMA (purchased from AVT) as a control;(2) structure lipids: e.g., Cholesterol (purchased from Sigma-Aldrich);(3) phospholipids: e.g., DSPC i.e.,1,2-distearoyl-SN-glycero-3-phosphocholine(Distearoylphosphatidylcholine, purchased from AVT); (4) polyethyleneglycolated lipids: e.g. DMG-PEG2000 i.e.,dimyristoylglycero-polyethylene glycol 2000(1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000,purchased from AVT); (5) active ingredients of nucleic acid fragments:e.g. Luciferase mRNA, siRNA, CRISPR Cas 9 mRNA, etc. (manufacturedin-house). The names of materials of the lipid nanoparticle assembly andtheir structural formulae are detailed in Table 4.

TABLE 4 No. Name Structural formula 1 DLin-MC3- DMA

2 Cholesterol

3 DSPC

4 DMG- PEG2000

Lipid nanoparticles were prepared by (1) dissolving and mixing ionizablelipid compounds, cholesterol, phospholipids and polyethylene glycolatedlipids in ethanol at (molar percentages) 50%, 38.5%, 10% and 1.5%,respectively; (2) dissolving the mRNA active ingredient in 25 mM sodiumacetate solution (pH=4.5); (3) using an automated high-throughputmicrofluidic system to mix the organic phase containing the lipidmixture and the aqueous phase containing the mRNA component in the flowratio range of 1:1 to 1:4 at a mixing speed of 10 mL/min to 18 mL/min;(4) the prepared lipid nanoparticles (N/P ratio of 6) were diluted withphosphate buffer solution and the nanoparticle solutions wereultrafiltered to the original preparation volume using ultrafiltrationtubes (purchased from Millipore) with a cut-off molecular weight of 30kDa; and (5) the obtained nanoparticles were filtered through a sterile0.2 μm filter membrane and then stored in a sealed glass vial at lowtemperature.

The preparation method of lipid nanoparticles includes microfluidicmixing systems, but is not limited to this method, which also includesT-type mixers and ethanol injection method, and the like.

Assay Example 2: Characterization of Physical Properties of LipidNanoparticles

The particle size and particle size dispersity index (PDI) of theprepared lipid nanoparticles were measured using a Zetasizer Pro(purchased from Malvern Instruments Ltd) and a DynaPro NanoStar(purchased from Wyatt) dynamic light scattering instrument. The degreeof RNA encapsulation by lipid nanoparticles was characterized by theEncapsulation Efficiency %, which reflects the degree of binding oflipid nanoparticles to RNA fragments. This parameter was measured by themethod of Quant-It™ RiboGreen RNA Assay (purchased from Invitrogen).Lipid nanoparticle samples were diluted in TE buffer (10 mM Tris-HCl, 1mM EDTA, pH=7.5). A portion of the sample solution was removed, to which0.5% Triton (Triton X-100) was added, and then allowed to stand at 37°C. for 30 minutes. Immediately after the addition of RIBOGREEN® reactionsolution, the fluorescence values were read on a Varioskan LUXmultifunctional microplate reader (purchased from Thermofisher) at 485nm for absorption and 528 nm for emission to give the encapsulationefficiency values.

Assay Example 3: Animal Experiment

The delivery effect and safety of nanoparticles encapsulated withluciferase mRNA (Trilink, L-7202) in mice were evaluated. The test micewere SPF-grade C57BL/6 mice, female, 6-8 weeks old, weighing 18-22 g,and were purchased from SPF (Beijing) Biotechnology Co., Ltd. Allanimals were acclimatized for more than 7 days prior to the experiment,and had free access to food and water during the experiment. Theconditions include alternating light and dark for 12/12 h, the indoortemperature of 20-26° C. and the humidity of 40-70%. The mice wererandomly grouped. The lipid nanoparticles encapsulated with luciferasemRNA prepared above were injected into mice by intravenousadministration at a single dose of 0.5 mg/kg mRNA, and the mice weresubjected to in vivo bioluminescence assay using a Small Animal In VivoImaging System (IVIS LUMINA III, purchased from PerkinElmer) at 6 hafter administration. The assay was performed as follows: D-luciferinsolution was prepared in saline at a concentration of 15 mg/mL, and eachmouse was given the substrate by intraperitoneal injection. At tenminutes after administration of the substrate, the mice wereanesthetized in an anesthesia chamber with isoflurane at a concentrationof 2.5%. The anesthetized mice were placed in IVIS for fluorescenceimaging, and data acquisition and analysis were performed on theconcentrated distribution area of fluorescence.

The in vivo delivery efficiency of lipid nanoparticle carriers wasexpressed as the mean values of fluorescence intensity and total photoncount in different animals within the same subject group, as shown inTable 5. Higher values of fluorescence intensity and total photon countindicate higher in vivo delivery efficiency of this mRNA fragment bylipid nanoparticles. The lipid nanoparticles containing the cationiclipids of the present disclosure have good in vivo delivery efficiency.Unexpectedly, compared with the molecule without tetramethyl, thecorresponding lipid nanoparticles of the present disclosure havesignificantly increased in vivo delivery efficiency, e.g., compound 20vs. D1, compound 46 vs. D2.

TABLE 5 Total photon Particle Encap- count in vivo Cationic Particlesize sulation at 6 hours after lipid size dispersity efficiencyadministration compound (nm) (PDI) (%) (Total Flux) 1 80.07 0.06 91.54 6.43E+08 2 229.35 0.03 79.14  4.23E+08 3 133.80 0.04 86.88  1.75E+09 6106.18 0.05 90.26  2.25E+09 7 203.67 0.04 69.51  1.16E+08 8 127.82 0.0760.36  3.26E+07 9 352.82 0.07 19.41  6.05E+06 10 118.59 0.07 53.83 1.26E+09 11 46.49 0.03 95.61  4.42E+06 12 89.34 0.07 85.02  1.10E+09 13157.10 0.08 56.65  1.08E+06 14 306.07 0.08 45.66  6.34E+07 15 91.68 0.0684.78  4.89E+08 16 55.39 0.05 96.52  3.97E+07 17 81.43 0.12 30.95 6.77E+05 18 161.29 0.05 87.86  1.14E+10 19 135.15 0.19 67.96  3.20E+0920 99.61 0.10 71.93  2.40E+10 23 151.35 0.07 70.22  1.43E+10 24 133.720.04 60.98  5.56E+09 25 236.90 0.06 32.43  1.89E+08 26 96.69 0.0581.29 >4.00E+10 27 105.70 0.05 88.99  2.20E+10 28 138.16 0.06 80.36 3.21E+09 32 116.61 0.07 99.02  7.30E+09 33 105.84 0.04 88.67  2.12E+0834 104.71 0.04 90.29  1.26E+10 36 88.33 0.07 97.52  4.84E+09 37 92.180.03 89.07  7.88E+09 40 83.90 0.05 97.06  4.22E+09 41 104.27 0.05 93.91 2.19E+10 42 152.04 0.07 71.95  5.32E+09 46 97.30 0.09 95.68 >4.00E+1090 18.17 0.05 83.21  1.04E+07 91 32.61 0.05 102.99  1.29E+06 92 107.560.05 91.66  2.13E+09 97 157.00 0.25 93.72  3.37E+09 98 107.87 0.13 93.28 2.12E+10 99 139.99 0.05 90.69  5.30E+09 100 118.19 0.07 83.29  1.18E+10101 152.45 0.06 76.09  5.19E+09 102 102.18 0.03 90.03  2.03E+10 103148.67 0.04 90.97  5.69E+09 104 71.14 0.06 85.54  2.61E+10 105 78.800.05 94.67  3.33E+09 106 83.09 0.05 85.65  1.85E+10 107 99.54 0.05 83.74 1.36E+10 108 121.41 0.05 92.63  1.21E+10 109 101.04 0.06 87.11 1.32E+10 110 97.59 0.01 92.65  2.06E+08 111 141.30 0.06 95.12  1.79E+10112 121.05 0.08 94.41  3.53E+10 113 112.65 0.03 94.77  3.59E+08 11472.32 0.04 93.41  1.06E+08 115 77.12 0.04 91.76  2.56E+10 116 88.62 0.0589.36 >4.00E+10 117 127.31 0.06 95.29  4.48E+09 118 88.33 0.07 93.87 3.14E+10 119 80.98 0.05 86.92  3.25E+10 120 98.99 0.07 95.55  3.15E+10121 103.57 0.06 93.62 >4.00E+10 122 96.72 0.07 91.76 >4.00E+10 123 84.980.05 92.27 >4.00E+10 125 95.69 0.07 89.45  1.99E+10 126 133.76 0.0694.35  1.77E+10 127 83.01 0.05 62.35  3.59E+10 128 83.10 0.05 79.88 1.00E+10 129 112.08 0.06 57.87  7.82E+09 DLin- 96.83 0.04 95.62 8.04E+09 MC3-D   MA   D1 131.2 0.18 97.08  4.45E+07 D2 245.33 0.2079.63  1.57E+09

Assay Example 4: Evaluation of Delivery Efficiency and Safely In Vitro

The delivery effect and safety of nanoparticles encapsulated withluciferase mRNA were evaluated at the cellular level in vitro. The cellsused in the assay were human embryonic kidney cells 293 (HEKi293T cells)cultured in DMEM (Dulbecco's Modified Eagle Medium) (purchased fromThermo Fisher) containing 1000 fetal bovine serum and 500penicillin-streptomycin double antibiotics at a indoor temperature of37° C. and a CO₂ concentration of 500. The cells were uniformlydispersed and spread in 48-well plates, and incubated in the incubatorfor 24 h. Then a solution of the lipid nanoparticles encapsulated withluciferase mRNA were added. After 24 h, the cells were lysed, and theintracellular expression intensity and relative light units (RLU) ofluciferase in each type of lipid nanoparticles were measured with aluciferase detection reagent (purchased from Promega). The higher theintensity of expression, the higher the delivery efficiency of the lipidmaterial at the cellular level. Meanwhile, CCK-8 reagent (purchased fromDOJINDO) was used in cytotoxicity testing for the parallel lipidnanoparticle-treated cell groups after 24 hours. In the test, the groupof cells to which only PBS was added was used as a negative control. Theprocedure was as follows: after the addition of CCK-8 solution, thecells were left to stand in an incubator at 37° C. for 4 h. Theabsorbance values were read on a multifunctional microplate reader at anabsorbance band of 450 nm. The ratio of the absorbance value of thenanoparticle-treated cells to that of the negative control was used as acharacterization parameter for cell viability.

The delivery effects and the toxicity data of nanoparticles at thecellular level in vitro are shown in Table 6.

TABLE 6 Cell fluorescence Cationic lipids intensity (RLU) Cell viability(%) 32 6.99E+06 96.25 37 1.04E+07 97.48 41 1.23E+07 104.91 100 1.98E+06104.67 DLin-MC3-DMA 2.95E+06 97.84

While the present disclosure has been fully described by way of itsembodiments, it is worth noting that various variations andmodifications are apparent to those skilled in the art. Such variationsand modifications should all be included within the scope of the claimsappended to this disclosure.

What is claimed is:
 1. A compound of formula (IV), or a pharmaceuticallyacceptable salt, isotopic variant, tautomer or stereoisomer thereof:

wherein, M₁ and M₂ are independently selected from —C(O)O—, —O—,—SC(O)O—, —OC(O)NR_(a)—, —NR_(a)C(O)NR_(a)—, —OC(O)S—, —OC(O)O—,—NR_(a)C(O)O—, —OC(O)—, —SC(O)—, —C(O)S—, —NR_(a)—, —C(O)NR_(a)—,—NR_(a)C(O)—, —NR_(a)C(O)S—, —SC(O)NR_(a)—, —C(O)—, —OC(S)—, —C(S)O—,—OC(S)NR_(a)—, —NR_(a)C(S)O—, —S—S— and —S(O)₀₋₂—; Q is selected from achemical bond, —C(O)O—, —O—, —SC(O)O—, —OC(O)NR_(b)—,—NR_(b)C(O)NR_(b)—, —OC(O)S—, —OC(O)O—, —NR_(b)C(O)O—, —OC(O)—, —SC(O)—,—C(O)S—, —NR_(b)—, —C(O)NR_(b)—, —NR_(b)C(O)—, —NR_(b)C(O)S—,—SC(O)NR_(b)—, —C(O)—, —OC(S)—, —C(S)O—, —OC(S)NR_(b)—, —NR_(b)C(S)O—,—S—S—, —S(O)₀₋₂—, phenylene and pyridylidene, wherein, the phenylene orpyridylidene is optionally substituted with one or more R*; G₅ is achemical bond or C₁₋₈ alkylene, which is optionally substituted with oneor more R**; G_(6a) and G_(6b) are independently a chemical bond or C₁₋₇alkylene, which is optionally substituted with one or more R**; G_(6a)and G_(6b) have a total length of 0, 1, 2, 3, 4, 5, 6 or 7 carbon atoms;R₉, R₁₀ and R** are independently H, C₁₋₈ alkyl, -L_(c)-OR_(c),-L_(c)-SR_(c) or -L_(c)-NR_(c)R′_(c); G₁, G₂, G₃ and G₄ areindependently a chemical bond, C₁₋₁₃ alkylene, C₂₋₁₃ alkenylene or C₂₋₁₃alkynylene, which is optionally substituted with one or more R^(s); G₁and G₂ have a total length of 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13carbon atoms; G₃ and G₄ have a total length of 3, 4, 5, 6, 7, 8, 9, 10,11, 12 or 13 carbon atoms; R₃ and R₄ are independently H, C₁₋₁₀ alkyl,C₁₋₁₀ haloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, 3- to 14-memberedcycloalkyl, 3- to 14-membered heterocyclyl, C₆₋₁₀ aryl or 5- to14-membered heteroaryl, which is optionally substituted with one or moreR*: or, R₃ and R₄ are taken together with the N atom to which they areattached to form 3- to 14-membered heterocyclyl, which is optionallysubstituted with one or more R*; or, R₄ and R₉ are taken together withthe atoms to which they are attached to form 3- to 14-memberedheterocyclyl or 5- to 14-membered heteroaryl, which is optionallysubstituted with one or more R*; R* is independently H, halogen, cyano,C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, -L_(b)-OR_(b), -L_(b)-SR_(b) or-L_(b)-NR_(b)R′_(b); R₅, R₆, R₇ and R₈ are independently C₁₋₈ alkyl,which is optionally substituted with one or more R*; R₁ and R₂ areindependently C₄₋₂₀ alkyl, C₄₋₂₀ alkenyl or C₄₋₂₀ alkynyl, which isoptionally substituted with one or more R, and wherein one or moremethylene units are optionally and independently replaced with —NR″—;R^(s) is independently H, C₁₋₁₄ alkyl, -L_(d)-OR_(d), -L_(d)-SR_(d) or-L_(d)-NR_(d)R′_(d); R is independently H, C₁₋₂₀ alkyl, -L_(a)-OR_(a),-L_(a)-SR_(a) or -L_(a)-NR_(a)R′_(a); R″ is independently H or C₁₋₂₀alkyl; L_(a) and L_(e) are independently a chemical bond or C₁₋₂₀alkylene; L_(b) and L_(f) are independently a chemical bond or C₁₋₁₀alkylene; L_(e) is independently a chemical bond or C₁₋₈ alkylene; L_(a)is independently a chemical bond or C₁₋₁₄ alkylene; R_(a) and R′_(a) areindependently H, C₁₋₂₀ alkyl, 3- to 14-membered cycloalkyl, and 3- to14-membered heterocyclyl, which are optionally substituted with one ormore of the following substituents: H, C₁₋₂₀ alkyl, -L_(e)-OR_(c),-L_(e)-SR_(e) and -L_(e)-NR_(e)R′_(e); R_(b) and R′_(b) areindependently selected from H, C₁₋₁₀ alkyl, 3- to 14-memberedcycloalkyl, and 3- to 14-membered heterocyclyl, which are optionallysubstituted with one or more of the following substituents: H, C₁₋₁₀alkyl, -L_(f)-OR_(f), -L_(f)-SR_(f) and -L_(f)-NR_(f)R′_(f); R_(c) andR′_(c) are independently H or C₁₋₈ alkyl; R_(d) and R′_(a) areindependently H or C₁₋₁₄ alkyl; R_(e) and R′_(e) are independently H orC₁₋₂₀ alkyl; R_(f) and R′_(f) are independently H or C₁₋₁₀ alkyl.
 2. Thecompound of formula (IV) of claim 1, or a pharmaceutically acceptablesalt, isotopic variant, tautomer or stereoisomer thereof, which has thestructure of formula (V):

wherein, Q is selected from —C(O)O—, —O—, —SC(O)O—, —OC(O)NR_(b)—,—NR_(b)C(O)NR_(b)—, —OC(O)S—, —OC(O)O—, —NR_(b)C(O)O—, —OC(O)—, —SC(O)—,—C(O)S—, —NR_(b)—, —C(O)NR_(b)—, —NR_(b)C(O)—, —NR_(b)C(O)S—,—SC(O)NR_(b)—, —C(O)—, —OC(S)—, —C(S)O—, —OC(S)NR_(b)—, —NR_(b)C(S)O—,—S—S—, and —S(O)₀₋₂—; G_(6a) and G_(6b) are independently a chemicalbond or C₁₋₅ alkylene, which is optionally substituted with 1, 2, 3 or 4R**; G_(6a) and G_(6b) have a total length of 0, 1, 2, 3, 4 or 5 carbonatoms; R₉ and R** are independently H, C₁₋₆ alkyl, -L_(c)-OR_(c) or-L_(c)-NR_(c)R′_(c); one of L₃ and L₅, or one of L₄ and L₆ is—(CR^(s)R^(s′))₂—, —CH═CH—, or —C≡C—, and the other is a chemical bond;G_(1a), G_(1b), G₂a, G₂b, G_(3a), G_(3b), G_(4a) and G_(4b) areindependently a chemical bond or C₁₋₇ alkylene, which is optionallysubstituted with 1, 2, 3, 4 or 5 R^(s); G_(1a), G_(1b), G_(2a) andG_(2b) have a total length of 1, 2, 3, 4, 5, 6 or 7 carbon atoms;G_(3a), G_(3b), G_(4a) and G_(4b) have a total length of 1, 2, 3, 4, 5,6 or 7 carbon atoms; R₃ and R₄ are independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, 3- to 10-membered cycloalkyl and 3- to10-membered heterocyclyl, which is optionally substituted with 1, 2, 3,4 or 5 R*; or, R₃ and R₄ are taken together with the N atom to whichthey are attached to form 3- to 10-membered heterocyclyl, which isoptionally substituted with 1, 2, 3, 4 or 5 R*; or, R₄ and R₉ are takentogether with the atoms to which they are attached to form 3- to10-membered heterocyclyl, which is optionally substituted with 1, 2, 3,4 or 5 R*; R* is independently H, halogen, cyano, C₁₋₆ alkyl, C₁₋₆haloalkyl, -L_(b)-OR_(b) or -L_(b)-NR_(b)R′_(b); R₅, R₆, R₇ and R₈ areindependently C₁₋₆ alkyl, which is optionally substituted with 1, 2, 3,4 or 5 R*; Y₁ and Y₂ are independently O, S or NR_(a); L₁ and L₂ areindependently —(CRR′)₂—, —CH═CH—, —C≡C— or —NR″—; G₇, G₈, G₉ and G₁₀ areindependently a chemical bond or C₁₋₁₂ alkylene, which is optionallysubstituted with 1, 2, 3, 4, 5 or 6 R; G₇ and G₈ have a total length of4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms; G₉ and G₁₀ have a totallength of 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms; 1, 2 or 3methylenes in G₇, G₈, G₉ or G₁₀ are optionally and independentlysubstituted with 1 R; R^(s) and R^(s′) are independently H, C₁₋₁₀ alkyl,-L_(d)-OR_(d) or -L_(d)-NR_(d)R′_(d); R and R′ are independently H,C₁₋₁₄ alkyl, -L_(a)-OR_(a) or -L_(a)-NR_(a)R′_(a); R″ is independently Hor C₁₋₁₄ alkyl; L_(a) is independently a chemical bond or C₁₋₁₄alkylene; L_(b) is independently a chemical bond or C₁₋₆ alkylene; L, isindependently a chemical bond or C₁₋₆ alkylene; L_(a) is independently achemical bond or C₁₋₁₀ alkylene; R_(a) and R′_(a) are independently H,C₁₋₁₄ alkyl, 3- to 10-membered cycloalkyl or 3- to 10-memberedheterocyclyl; R_(b) and R′_(b) are independently H, C₁₋₆ alkyl, 3- to10-membered cycloalkyl or 3- to 10-membered heterocyclyl; R_(e) andR′_(c) are independently H or C₁₋₆ alkyl; R_(d) and R′_(a) areindependently H or C₁₋₁₀ alkyl.
 3. The compound of formula (V) of claim2, or a pharmaceutically acceptable salt, isotopic variant, tautomer orstereoisomer thereof, wherein, Q is selected from —C(O)O—, —O—,—SC(O)O—, —OC(O)NH—, —NHC(O)NH—, —OC(O)S—, —OC(O)O—, —NHC(O)O—, —OC(O)—,—SC(O)—, —C(O)S—, —NH—, —C(O)NH—, —NHC(O)—, —NHC(O)S—, —SC(O)NH—,—C(O)—, —OC(S)—, —C(S)O—, —OC(S)NH— and —NHC(S)O—; G_(6a) is a chemicalbond or C₁₋₄ alkylene, which is optionally substituted with 1, 2, 3 or 4R**; G_(6b) is a chemical bond or C₁₋₂ alkylene, which is optionallysubstituted with 1 or 2 R**; G_(6a) and G_(6b) have a total length of 0,1, 2, 3 or 4 carbon atoms; R₉ and R** are independently H or C₁₋₆ alkyl;one of L₃ and L₅, or one of L₄ and L₆ is —(CHR^(s))₂—, —CH═CH— or —C≡C—,and the other is a chemical bond; G_(1a) and G_(3a) are independently achemical bond or C₁₋₇ alkylene; G_(1b) and G_(3b) are independently achemical bond or C₁₋₃ alkylene; G_(2a) and G_(4a) are independently achemical bond or C₁₋₃ alkylene; G_(2b) and G_(4b) are independently achemical bond or C₁₋₄ alkylene; G_(1a), G_(1b), G_(2a) and G_(2b) have atotal length of 1, 2, 3, 4, 5, 6 or 7 carbon atoms; G_(3a), G_(3b),G_(4a) and G_(4b) have a total length of 1, 2, 3, 4, 5, 6 or 7 carbonatoms; R₃ and R₄ are independently H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, 3- to7-membered cycloalkyl or 3- to 7-membered heterocyclyl, which isoptionally substituted with 1, 2, 3, 4 or 5 R*; or, R₃ and R₄ are takentogether with the N atom to which they are attached to form 3- to7-membered heterocyclyl, which is optionally substituted with 1, 2, 3, 4or 5 R*; or, R₄ and R₉ are taken together with the atoms to which theyare attached to form 3- to 7-membered heterocyclyl, which is optionallysubstituted with 1, 2, 3, 4 or 5 R*; R* is independently H, halogen,cyano, C₁₋₆ alkyl, C₁₋₆ haloalkyl, -L_(b)-OR_(b) or -L_(b)-NR_(b)R′_(b);R₅, R₆, R₇ and R₈ are independently C₁₋₆ alkyl; Y₁ and Y₂ areindependently O, S or NR_(a); L₁ and L₂ are independently —(CHR)₂—,—CH═CH—, —C≡C— or —NR″—; G₇ and G₉ are independently a chemical bond orC₁₋₆ alkylene; G₈ and G₁₀ are independently C₁₋₁₀ alkylene; G₇ and G₈have a total length of 4, 5, 6, 7, 8, 9 or 10 carbon atoms; G₉ and G₁₀have a total length of 4, 5, 6, 7, 8, 9 or 10 carbon atoms; 1, 2 or 3methylenes in G₇, G₈, G₉ or G₁₀ are optionally and independentlysubstituted with 1 R; R^(s) is independently H or C₁₋₆ alkyl; R isindependently H or C₁₋₁₀ alkyl; R″ is independently H or C₁₋₁₀ alkyl;L_(b) is independently a chemical bond or C₁₋₆ alkylene; R_(a) isindependently H or C₁₋₁₀ alkyl; R_(b) and R′_(b) are independently H orC₁₋₆ alkyl; alternatively,

 is independently selected from the following groups: —(CH₂)₃—C(CH₃)₂—,—(CH₂)₄—C(CH₃)₂—, —(CH₂)₅—C(CH₃)₂—, —(CH₂)₆—C(CH₃)₂—, —(CH₂)₇—C(CH₃)₂—,—(CH₂)₈—C(CH₃)₂—, —(CH₂)₃—CH═CH—C(CH₃)₂—, —(CH₂)₃—C—C—C(CH₃)₂—,—(CH₂)₄—C(CH₃)₂—CH₂—, —(CH₂)₃—C(CH₃)₂—(CH₂)₂—, —(CH₂)₂—C(CH₃)₂—(CH₂)₃—,—(CH₂)₂—CH═CH—C(CH₃)₂—CH₂—, —(CH₂)₂—C(CH₃)₂—C—C—CH₂—,—(CH₂)₂—C(CH₃)₂—CH═CH—CH₂—, —(CH₂)₂—C—C—C(CH₃)₂—CH₂— and—(CH₂)₃—C(CH₃)₂—C≡C—; -G₇-L₁-G₈-H or -G₉-L₂-G₁₀-H is independentlyselected from the following groups: —(CH₂)₅CH₃, —(CH₂)₆CH₃, —(CH₂)₇CH₃,—(CH₂)₈CH₃, —(CH₂)₉CH₃, —(CH₂)₁₀CH₃, —(CH₂)₁₁CH₃, —CH₂—C≡C—(CH₂)₅CH₃,—CH₂—C≡C—(CH₂)₆CH₃, —(CH₂)₂—C≡C—(CH₂)₅CH₃, —(CH₂)₄—C≡C—(CH₂)₃CH₃,—CH₂—CH═CH—(CH₂)₅CH₃, —CH₂—CH═CH—(CH₂)₆CH₃, —(CH₂)₂—CH═CH—(CH₂)₅CH₃,—(CH₂)₄—CH═CH—(CH₂)₃CH₃, —(CH₂)₅—CH═CH—CH₂CH₃,


4. The compound of formula (IV) of claim 1, or a pharmaceuticallyacceptable salt, isotopic variant, tautomer or stereoisomer thereof,which has the structure of formula (VI) or formula (VII):

wherein, a, a′, b and g are independently 0, 1, 2, 3, 4 or 5, a′ and bare not 0 at the same time; a′+g=0, 1, 2, 3, 4 or 5; c and e areindependently 3, 4, 5, 6, 7, 8 or 9; d and f are independently 0, 1, 2,3 or 4; c+d=3, 4, 5, 6, 7, 8 or 9, e+f=3, 4, 5, 6, 7, 8 or 9; methylenesin

 or are optionally and independently substituted with 1, 2, 3, 4 or 5C₁₋₆ alkyl; R₃ and R₄ are independently H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,3- to 10-membered cycloalkyl or 3- to 10-membered heterocyclyl, which isoptionally substituted with 1, 2, 3, 4 or 5 R*; or, R₃ and R₄ are takentogether with the N atom to which they are attached to form 3- to10-membered heterocyclyl, which is optionally substituted with 1, 2, 3,4 or 5 R*; R* is independently H, halogen, cyano, C₁₋₆ alkyl, C₁₋₆haloalkyl, -L_(b)-OR_(b) or -L_(b)-NR_(b)R′_(b); R₅, R₆, R₇ and R₈ areindependently C₁₋₆ alkyl, which is optionally substituted with 1, 2, 3,4 or 5 R*; Y₁ and Y₂ are independently O, S or NR_(a); L₁ and L₂ areindependently —(CRR′)₂—, —CH═CH—, —C≡C— or —NR″—; G₇, G₈, G₉ and G₁₀ areindependently a chemical bond or C₁₋₁₂ alkylene, which is optionallysubstituted with 1, 2, 3, 4, 5 or 6 R; G₇ and G₈ have a total length of6, 7, 8, 9, 10, 11 or 12 carbon atoms; G₉ and G₁₀ have a total length of6, 7, 8, 9, 10, 11 or 12 carbon atoms; 1, 2 or 3 methylenes in G₇, G₈,G₉ or G₁₀ are optionally and independently substituted with 1 R; R andR′ are independently H, C₁₋₁₄ alkyl, -L_(a)-OR_(a) or-L_(a)-NR_(a)R′_(a); L_(a) is independently a chemical bond or C₁₋₁₄alkylene; L_(b) is independently a chemical bond or C₁₋₆ alkylene; R_(a)and R′_(a) are independently H, C₁₋₁₄ alkyl, 3- to 10-memberedcycloalkyl or 3- to 10-membered heterocyclyl; R_(b) and R′_(b) areindependently H, C₁₋₆ alkyl, 3- to 10-membered cycloalkyl or 3- to10-membered heterocyclyl; R″ is independently H or C₁₋₁₄ alkyl.
 5. Thecompound of formula (VI) or formula (VII) of claim 4, or apharmaceutically acceptable salt, isotopic variant, tautomer orstereoisomer thereof, wherein, a is 0, 1, 2, 3 or 4, alternatively 1, 2,3 or 4, alternatively 2, 3 or 4; a′ and b are independently 0, 1, 2, 3or 4, alternatively 2; g is 0, 1 or 2, alternatively 0 or 1; a′+g=0, 1,2, 3, 4 or 5, alternatively a′+g=2 or 3; c and e are independently 3, 4,5 or 6; d and f are independently 0, 1 or 2; c+d=4, 5 or 6, e+f=4, 5 or6; methylenes in

 are optionally and independently substituted with 1, 2, 3, 4 or 5 C₁₋₆alkyl; methylenes in

 are optionally and independently substituted with 1 or 2 C₁₋₆ alkyl; R₃and R₄ are independently C₁₋₆ alkyl, which is optionally substitutedwith 1, 2 or 3 R*; R* is independently H, C₁₋₆ alkyl, C₁₋₆ haloalkyl or—OR_(b); or, R₃ and R₄ are taken together with the N atom to which theyare attached to form 3- to 7-membered heterocyclyl, alternatively5-membered heterocyclyl, which is optionally substituted with 1, 2 or 3R*; R₅, R₆, R₇ and R₈ are independently C₁₋₆ alkyl, which is optionallysubstituted with 1, 2, 3, 4 or 5 R*; Y₁ and Y₂ are independently O, S orNR_(a), alternatively O or S; L₁ and L₂ are independently —(CHR)₂—,—CH═CH—, —C≡C— or —NR″—, alternatively —(CHR)₂—, —CH═CH— or —C≡C—; G₇and G₉ are independently a chemical bond or C₁₋₆ alkylene; G₈ and G₁₀are independently C₁₋₁₀ alkylene; G₇ and G₈ have a total length of 6, 7,8, 9 or 10 carbon atoms; G₉ and G₁₀ have a total length of 6, 7, 8, 9 or10 carbon atoms; 1, 2 or 3 methylenes in G₇, G₈, G₉ or G₁₀ areoptionally and independently substituted with 1 R; R is independently Hor C₁₋₈ alkyl; R″ is independently H or C₁₋₁₀ alkyl; R_(a) isindependently H or C₁₋₁₀ alkyl; R_(b) is independently H or C₁₋₆ alkyl,alternatively H.
 6. The compound of formula (VI) of claim 5, or apharmaceutically acceptable salt, isotopic variant, tautomer orstereoisomer thereof, wherein, a is 0, 1, 2, 3 or 4, alternatively 1, 2,3 or 4, alternatively 2, 3 or 4; c and e are independently 3, 4, 5 or 6;d and f are independently 0, 1 or 2; c+d=4, 5 or 6, e+f=4, 5 or 6; R₃and R₄ are independently C₁₋₆ alkyl; or, R₃ and R₄ are taken togetherwith the N atom to which they are attached to form 4- to 6-memberedheterocyclyl, alternatively 5-membered heterocyclyl, which is optionallysubstituted with 1, 2 or 3 R*; R* is independently H, C₁₋₆ alkyl or C₁₋₆haloalkyl; R₅, R₆, R₇ and R₈ are independently C₁₋₆ alkyl, which isoptionally substituted with 1, 2, 3, 4 or 5 R*; Y₁ and Y₂ areindependently O, S or NR_(a), alternatively O or S; L₁ and L₂ areindependently —(CHR)₂—, —CH═CH—, —C≡C— or —NR″—, alternatively —(CHR)₂—,—CH═CH— or —C≡C—; G₇ and G₉ are independently a chemical bond or C₁₋₅alkylene; G₈ and G₁₀ are independently C₁₋₈ alkylene; G₇ and G₈ have atotal length of 6, 7, 8, 9 or 10 carbon atoms; G₉ and G₁₀ have a totallength of 6, 7, 8, 9 or 10 carbon atoms; 1, 2 or 3 methylenes in G₇, G₈,G₉ or G₁₀ are optionally and independently substituted with 1 R; R isindependently H or C₁₋₈ alkyl, alternatively H or C₁₋₇ alkyl,alternatively H or C₁₋₆ alkyl; R″ is independently H or C₇₋₉ alkyl;R_(a) is independently H or C₈₋₁₀ alkyl.
 7. The compound of formula (VI)of claim 6, or a pharmaceutically acceptable salt, isotopic variant,tautomer or stereoisomer thereof, wherein, a is 2, 3 or 4; c and e areindependently 3, 4, 5 or 6; d and f are independently 0, 1 or 2; c+d=4,5 or 6, e+f=4, 5 or 6; R₃ and R₄ are independently C₁₋₆ alkyl; R₅, R₆,R₇ and R₈ are independently C₁₋₆ alkyl; Y₁ and Y₂ are independently O orS; L₁ and L₂ are independently —(CHR)₂—, —CH═CH— or —C≡C—; G₇ and G₉ areindependently C₁₋₄ alkylene; G₈ and G₁₀ are independently C₂₋₇ alkylene;G₇ and G₈ have a total length of 6, 7 or 8 carbon atoms; G₉ and G₁₀ havea total length of 6, 7 or 8 carbon atoms; 1, 2 or 3 methylenes in G₇,G₈, G₉ or G₁₀ are optionally and independently substituted with 1 R; Ris independently H or C₁₋₇ alkyl; provided that, when L₁ is —C≡C—, thenG₇ is C₁₋₂ alkylene, or when L₂ is —C≡C—, then G₉ is C₁₋₂ alkylene. 8.The compound of formula (VI) of claim 6, or a pharmaceuticallyacceptable salt, isotopic variant, tautomer or stereoisomer thereof,wherein, a is 2, 3 or 4, alternatively 2 or 3; c and e are independently4, 5 or 6; d and fare 0; R₃ and R₄ are independently C₁₋₆ alkyl; R₅, R₆,R₇ and R₈ are independently C₁₋₆ alkyl; Y₁ and Y₂ are O; L₁ and L₂ areindependently —(CHR)₂— or —CH═CH—; G₇ and G₉ are independently —CH₂— or—CH₂CHR—; G₈ and G₁₀ are independently —(CH₂)₆— or —(CH₂)₇—; G₇ and G₈have a total length of 7 or 8 carbon atoms; G₉ and G₁₀ have a totallength of 7 or 8 carbon atoms; 1, 2 or 3 methylenes in G₈ or G₁₀ areoptionally and independently substituted with 1 R; R is independently Hor C₄₋₆ alkyl, alternatively H or C₅ alkyl; alternatively -G₇-L₁-G₈-Hand -G₉-L₂-G₁₀-H are not —(CH₂)₉CH₃ at the same time.
 9. The compound offormula (VI) of claim 6, or a pharmaceutically acceptable salt, isotopicvariant, tautomer or stereoisomer thereof, wherein, a is 2; c and e areindependently 4, 5 or 6, alternatively 5; d and fare 0; R₃ and R₄ areindependently C₁₋₆ alkyl; R₅, R₆, R₇ and R₈ are independently C₁₋₆alkyl; Y₁ and Y₂ are independently O or S; one of L₁ and L₂ is —C≡C—,the other is —(CHR)₂—, or both of L₁ and L₂ are —C≡C—; alternatively oneof L₁ and L₂ is —C≡C—, the other is —(CHR)₂—; G₇ and G₉ are —CH₂—; G₈and G₁₀ are independently —(CH₂)₆— or —(CH₂)₇—; 1 methylene in G₈ or G₁₀is optionally and independently substituted with 1 R, alternatively G₈and G₁₀ are independently —CHR—(CH₂)₅—, —CHR—(CH₂)₆—, —CH₂—CHR—(CH₂)₄—or —(CH₂)₂—CHR—(CH₂)₄—; R is independently H or C₄₋₆ alkyl,alternatively H or C₅ alkyl; provided that, only one of the -G₇-L₁-G₈-Hand -G₉-L₂-G₁₀-H is substituted with one non-hydrogen R substituent andthe other is unsubstituted.
 10. The compound of formula (VI) of claim 6,or a pharmaceutically acceptable salt, isotopic variant, tautomer orstereoisomer thereof, wherein, a is 2; c and e are independently 4, 5 or6, alternatively 5; d and fare 0; R₃ and R₄ are independently C₁₋₃alkyl, alternatively Me; R₅, R₆, R₇ and R₈ are independently C₁₋₃ alkyl,alternatively Me; Y₁ and Y₂ are independently O or S, alternatively 0;both of L₁ and L₂ are —C≡C—; G₇ and G₉ are —CH₂—; G₈ and G₁₀ areindependently —(CH₂)₆— or —(CH₂)₇—, alternatively —(CH₂)₇—.
 11. Thecompound of formula (VI) of claim 6, or a pharmaceutically acceptablesalt, isotopic variant, tautomer or stereoisomer thereof, wherein, a is2; c and e are 3; d and fare 2; R₃ and R₄ are independently C₁₋₃ alkyl,alternatively Me; R₅, R₆, R₇ and R₈ are independently C₁₋₃ alkyl; Y₁ andY₂ are independently O or S, alternatively 0; L₁ and L₂ are —(CHR)₂—; G₇and G₉ are independently —CH₂— or —CH₂CHR—; G₈ and G₁₀ are independently—(CH₂)₅—, —(CH₂)₆— or —(CH₂)₇—; G₇ and G₈ have a total length of 6, 7 or8 carbon atoms, alternatively 7 carbon atoms; G₉ and G₁₀ have a totallength of 6, 7 or 8 carbon atoms, alternatively 7 carbon atoms; 1, 2 or3 methylenes in G₈ or G₁₀ are optionally and independently substitutedwith 1 R; R is independently H or C₁₋₇ alkyl, alternatively H or C₁₋₆alkyl, alternatively Me.
 12. The compound of formula (VI) of claim 6, ora pharmaceutically acceptable salt, isotopic variant, tautomer orstereoisomer thereof, wherein, a is 2; c and e are 4, 5, or 6,alternatively 5; d and fare 0; R₃ and R₄ are independently C₁₋₆ alkyl;R₅, R₆, R₇ and R₈ are independently C₁₋₆ alkyl; Y₁ and Y₂ are S; L₁ andL₂ are —(CHR)₂—; G₇ and G₉ are independently —CH₂— or —CH₂CHR—; G₈ andG₁₀ are independently —(CH₂)₅—, —(CH₂)₆— or —(CH₂)₇—; G₇ and G₈ have atotal length of 7 or 8 carbon atoms, alternatively 8 carbon atoms; G₉and G₁₀ have a total length of 7 or 8 carbon atoms, alternatively 8carbon atoms; 1, 2 or 3 methylenes in G₈ or G₁₀ are optionally andindependently substituted with 1 R; R is independently H or C₄₋₆ alkyl,alternatively H or C₅ alkyl.
 13. The compound of formula (VII) of claim5, or a pharmaceutically acceptable salt, isotopic variant, tautomer orstereoisomer thereof, wherein, a′ and b are 2; g is 0 or 1; c and e are5; d and fare 0; R₃ is C₁₋₆ alkyl, which is optionally substituted with1, 2 or 3 R*; R* is independently H, C₁₋₆ alkyl, C₁₋₆ haloalkyl or—OR_(b), alternatively H, C₁₋₆ alkyl or C₁₋₆ haloalkyl; R₅, R₆, R₇ andR₈ are independently C₁₋₃ alkyl; Y₁ and Y₂ are independently O or S; L₁and L₂ are —(CHR)₂—; G₇ and G₉ are independently —CH₂— or —CH₂CHR—; G₈and G₁₀ are independently —(CH₂)₅—, —(CH₂)₆— or —(CH₂)₇—; G₇ and G₈ havea total length of 6, 7 or 8 carbon atoms; G₉ and G₁₀ have a total lengthof 6, 7 or 8 carbon atoms; 1, 2 or 3 methylenes in G₈ or G₁₀ areoptionally and independently substituted with 1 R; R is independently Hor C₄₋₆ alkyl; R_(b) is independently H or C₁₋₆ alkyl, alternatively H.14. The compound of formula (VII) of claim 13, or a pharmaceuticallyacceptable salt, isotopic variant, tautomer or stereoisomer thereof,wherein, R₃ is Me or —CH₂CH₃, alternatively Me; both of Y₁ and Y₂ are O;G₇ and G₈ have a total length of 6 or 7 carbon atoms, alternatively 7carbon atoms; G₉ and G₁₀ have a total length of 6 or 7 carbon atoms,alternatively 7 carbon atoms.
 15. The compound of formula (VII) of claim13, or a pharmaceutically acceptable salt, isotopic variant, tautomer orstereoisomer thereof, wherein, R₃ is Me or —CH₂CH₃; Y₁ and Y₂ areindependently O or S, where Y₁ and Y₂ are not O at the same time; G₇ andG₈ have a total length of 6, 7 or 8 carbon atoms; G₉ and G₁₀ have atotal length of 6, 7 or 8 carbon atoms.
 16. The compound of formula(VII) of claim 15, or a pharmaceutically acceptable salt, isotopicvariant, tautomer or stereoisomer thereof, wherein, g is 0 or 1,alternatively 1; R₃ is Me or —CH₂CH₃, alternatively Me; one of Y₁ and Y₂is O, and the other is S; G₇ and G₈ have a total length of 7 carbonatoms; G₉ and G₁₀ have a total length of 7 carbon atoms.
 17. Thecompound of formula (VII) of claim 15, or a pharmaceutically acceptablesalt, isotopic variant, tautomer or stereoisomer thereof, wherein, g is0 or 1, alternatively 0; R₃ is Me or —CH₂CH₃; both of Y₁ and Y₂ are S;G₇ and G₈ have a total length of 7 or 8 carbon atoms; G₉ and G₁₀ have atotal length of 7 or 8 carbon atoms.
 18. The compound of formula (IV) ofclaim 1, or a pharmaceutically acceptable salt, isotopic variant,tautomer or stereoisomer thereof, wherein, the compound is selected fromthe following:

or a pharmaceutically acceptable salt, isotopic variant, tautomer orstereoisomer thereof.
 19. A pharmaceutical composition, comprising thecompound of claim 1, or a pharmaceutically acceptable salt, isotopicvariant, tautomer or stereoisomer thereof, and pharmaceuticallyacceptable excipient(s).
 20. A method of treating, diagnosing, orpreventing a disease in a subject, comprising administering to thesubject the pharmaceutical composition of claim
 19. 21. A method ofdelivering a load in a subject, comprising administering to the subjectthe pharmaceutical composition of claim 19; wherein, the load is one ormore of therapeutic, prophylactic or diagnostic agents.
 22. The methodof claim 21, wherein, the therapeutic, prophylactic or diagnostic agentis a nucleic acid; alternatively, the nucleic acid is one or more ofASO, RNA or DNA; alternatively, the RNA is one or more of interferingRNA (RNAi), small interfering RNA (siRNA), short hairpin RNA (shRNA),antisense RNA (aRNA), messenger RNA (mRNA), modified messenger RNA(mmRNA), long non-coding RNA (lncRNA), microRNA (miRNA), smallactivating RNA (saRNA), multimeric coding nucleic acid (MCNA), polymericcoding nucleic acid (PCNA), guide RNA (gRNA), CRISPRRNA (crRNA) ornucleases, alternatively mRNA, more alternatively, modified mRNA.
 23. Amethod for preparing the compound of general formula (II), comprising:

reacting the compound of general formula (IIb) with the compound ofgeneral formula (IIc), to give the compound of general formula (II);wherein, G₁, G₂, G₃ or G₄ is independently a bond, C₁₋₂₀ alkyl, C₂₋₂₀alkenyl and C₂₋₂₀ alkynyl; G₆ is independently a bond or C₁₋₈ alkyl; M₁or M₂ is independently biodegradable groups; R₁ or R₂ is independentlyC₄₋₂₈ alkyl, C₄₋₂₈ alkenyl or C₄₋₂₈ alkynyl; R₃ or R₄ is independentlyH, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl orheteroaryl; or, R₃ and R₄ are taken together with the N atom to whichthey are attached to form 3- to 14-membered heterocyclyl; R₅, R₆, R₇ orR₈ is each independently C₁₋₈ alkyl; each of the alkyl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is eachindependently and optionally further substituted.
 24. A method ofpreparing the compound of general formula (II′), comprising:

reacting the compound of general formula (II′a) with the compound ofgeneral formula (II′b), to give the compound of general formula (II′);wherein, G₁, G₂, G₃ or G₄ is each independently a bond, C₁₋₂₀ alkyl,C₂₋₂₀ alkenyl and C₂₋₂₀ alkynyl; G₅ or G₆ is each independently a bondor C₁₋₈ alkyl; M₁ or M₂ is each independently biodegradable groups; R₁or R₂ is each independently C₄₋₂₈ alkyl, C₄₋₂₈ alkenyl or C₄₋₂₈ alkynyl;R′₃, R′₄, R′₅ or R′₆ is each independently C₁₋₈ alkyl; R′₇ is selectedfrom H, halogen, cyano, OH, oxo, C₁₋₆ alkyl, C₁₋₆ alkoxy, —NH₂, —NHC₁₋₆alkyl and —N(C₁₋₆ alkyl)₂; each of the alkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl or heteroaryl is each independently andoptionally further substituted.